Halogenopyrazoles as inhibitors of thrombin

ABSTRACT

There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of thrombin, which compounds include substituted pyrazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing a disease or disorder, which disease or disorder is amenable to treatment or prevention by the inhibition of thrombin.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a division of U.S. application Ser. No.14/776,641, filed on Sep. 14, 2015, which is a U.S. National Stage entryunder 35 U.S.C. § 371 of International Application No. PCT/US14/00058,filed on Mar. 17, 2014, which in turn claims priority to U.S.Provisional Application No. 61/789,358, filed on Mar. 15, 2013, and U.S.Provisional Application No. 61/899,588, filed on Nov. 4, 2013, each ofwhich is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

The present disclosure relates to compounds, e.g., multisubstitutedaromatic compounds, which exhibit biological activity, e.g., inhibitoryaction, against thrombin (activated blood-coagulation factor II; EC3.4.21.5).

In mammalian systems, blood vessel injuries result in bleeding events,which are dealt with by the blood coagulation cascade. The cascadeincludes the Extrinsic and Intrinsic pathways, involving the activationof at least 13 interconnected factors and a variety of co-factors andother regulatory proteins. Upon vascular injury, plasma factor VIIinteracts with exposed Tissue Factor (TF), and the resultant TF-fVIIacomplex initiates a complex series of events. Factor fXa is produceddirectly ‘downstream’ from the TF-fVIIa complex, and amplified manifoldvia the Intrinsic Pathway. FXa then serves as the catalyst for formationof thrombin (fIIa), which in turn is the direct precursor tofibrinolysis. The outcome is a fibrinolytic clot, which stops thebleeding. Fibrinolysis of the polymeric clot into fibrin monomers leadsto dissolution and a return of the system to the pre-clot state. Thecascade is a complex balance of factors and co-factors and is tightlyregulated.

In disease states, undesired up- or down-regulation of any factor leadsto conditions such as bleeding or thrombosis. Historically,anticoagulants have been used in patients at risk of suffering fromthrombotic complications, such as angina, stroke and heart attack.

Warfarin has enjoyed dominance as a first-in-line anticoagulanttherapeutic. Developed in the 1940s, it is a Vitamin K antagonist andinhibits factors II, VII, IX and X, amongst others. It is administeredorally, but its ease of use is tempered by other effects: it has a verylong half life (>2 days) and has serious drug-drug interactions.Importantly, since Vitamin K is a ubiquitous cofactor within thecoagulation cascade, antagonism results in the simultaneous inhibitionof many clotting factors and thus can lead to significant bleedingcomplications.

Much attention has been focused on heparin, the naturally-occurringpolysaccharide that activates AT III, the endogenous inhibitor of manyof the factors in the coagulation cascade. The need for parenteraladministration for the heparin-derived therapeutics, and theinconvenient requirements for close supervision for the orally availablewarfarin, has resulted in a drive to discover and develop orallyavailable drugs with wide therapeutic windows for safety and efficacy.

Indeed, the position of thrombin in the coagulation cascade has made ita popular target for drug discovery. Without wishing to be bound by anytheory, it is believed that the ultimate development of direct thrombininhibitors (DTIs) is usefully based upon the classical D-Phe-Pro-Argmotif, a sequence that mimics fibrinogen, which is a natural substrateof thrombin. Without further wishing to be bound by any theory, it isbelieved that the use of DTIs is very well precedented, such as with thehirudin-based anticoagulants, and thus there is strong interest in thediscovery and development of novel DTIs.

A thorough discussion of thrombin and its roles in the coagulationprocess can be found in a variety of references, including the followingwhich are incorporated herein by reference in their entireties and forall purposes: Wieland, H. A., et al., 2003, Curr Opin Investig Drugs,4:264-71; Gross, P. L. & Weitz, J. I., 2008, Arterioscler Thromb VascBiol, 28:380-6; Hirsh, J., et al., 2005, Blood, 105:453-63; Prezelj, A.,et al., 2007, Curr Pharm Des, 13:287-312.

BRIEF SUMMARY OF THE INVENTION

Embodiments of the invention encompass compounds with structure ofFormula (Ia):

or pharmaceutically acceptable salt, ester, solvate, or prodrug thereof;wherein Ring A can be substituted or unsubstituted pyrazolyl; L¹ and L³can be independently a bond, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO₂—, —O—,—NHSO₂—, or —NR⁴—; L² can be absent, a bond, substituted orunsubstituted alkylene, substituted or unsubstituted eteroalkylene, —S—,—SO—, —SO₂—, —O—, —NHSO₂—, or —NR⁴—; R¹ and R³ can be independentlyhydrogen, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstituted fusedring aryl, or substituted or unsubstituted heteroaryl; R² can be absent,hydrogen, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstituted fusedring aryl, or substituted or unsubstituted heteroaryl, provided thatwhen L² can be absent, R² can be absent; R⁴ can be hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkenyl, and substituted or unsubstituted fused ring aryl orsubstituted or unsubstituted heteroaryl; and Y can be a halogen. In someembodiments of the methods, L² and R² can be absent. In someembodiments, the compound can have the structure of Formula (IIa) orFormula (IIb):

In some embodiments where the compound can have the structure of Formula(IIa), L³ can be a bond, or substituted or unsubstituted alkylene, andR³ can be substituted or unsubstituted aryl, substituted orunsubstituted fused ring aryl, substituted or unsubstitutedheterocycloalkyl, or substituted or unsubstituted heteroaryl, and Y canbe fluorine. In some embodiments where the compound can have thestructure of Formula (IIa), L³ can be —C(O)O—, R³ can be substituted orunsubstituted alkyl, and Y can be fluorine. In some embodiments wherethe compound can have the structure of Formula (IIa), L³ can be—C(O)NR⁵—, R⁵ can be hydrogen or alkyl, R³ can be substituted orunsubstituted alkyl, or substituted or unsubstituted aryl, and Y can befluorine. In some embodiments, R³ can be substituted or unsubstitutedphenyl. In some embodiments, the heteroaryl can be pyridyl, pyridazinyl,pyrimidinyl, thienyl, or furyl. In some embodiments, R³ can bechloro-substituted thienyl. In some embodiments, the heterocycloalkylcan be morpholinyl, oxanyl, or oxetanyl. In some embodiments, the fusedring aryl can be benzodioxinyl or naphthyl. In some embodiments, L¹ canbe a bond, —S—, —NR⁴—, substituted or unsubstituted alkylene, orsubstituted or unsubstituted heteroalkylene, and R¹ can be hydrogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,substituted or unsubstituted fused ring aryl, substituted orunsubstituted heteroaryl, or substituted or unsubstitutedheterocycloalkyl. In some embodiments, the heteroaryl can be pyridyl,pyridazinyl, pyrimidinyl, thienyl, or furyl. In some embodiments, R¹ canbe chloro-substituted thienyl. In some embodiments, the heterocycloalkylcan be morpholinyl, oxanyl, or oxetanyl. In some embodiments, the fusedring aryl can be benzodioxinyl or naphthyl. In some embodiments, R¹ canbe substituted or unsubstituted phenyl. In some embodiments, L² can be abond, and R² can be hydrogen. In some embodiments, L² can be substitutedor unsubstituted alkylene or —C(O)—, and R² can be hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl,substituted or unsubstituted fused ring aryl, or substituted orunsubstituted heteroaryl. In some embodiments, the heteroaryl can bepyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl. In someembodiments, R² can be substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl, or substituted or unsubstitutedheterocycloalkyl. In some embodiments, the heterocycloalkyl can bemorpholinyl, oxanyl, or oxetanyl. In some embodiments, the fused ringaryl can be benzodioxinyl or naphthyl. In some embodiments, R² can besubstituted or unsubstituted phenyl.

In some embodiments where the compound can have the structure of Formula(IIb), L³ can be a bond, or substituted or unsubstituted alkylene, R³can be substituted or unsubstituted aryl, substituted or unsubstitutedfused ring aryl, substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted heteroaryl, and Y can be fluorine. In someembodiments where the compound can have the structure of Formula (IIa),L³ can be —C(O)O—, R³ can be substituted or unsubstituted alkyl, and Ycan be fluorine. In some embodiments where the compound can have thestructure of Formula (IIa), L³ can be —C(O)NR⁵—, R⁵ can be hydrogen oralkyl, R³ can be substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, and Y can be fluorine. In some embodiments, R³ canbe substituted or unsubstituted phenyl. In some embodiments, theheteroaryl can be pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl.In some embodiments, R³ can be chloro-substituted thienyl. In someembodiments, the heterocycloalkyl can be morpholinyl, oxanyl, oroxetanyl. In some embodiments, the fused ring aryl can be benzodioxinylor naphthyl. In some embodiments, L¹ can be a bond, —S—, —NR⁴—,substituted or unsubstituted alkylene, or substituted or unsubstitutedheteroalkylene, and R¹ can be hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted aryl, substituted or unsubstitutedfused ring aryl, substituted or unsubstituted heteroaryl, or substitutedor unsubstituted heterocycloalkyl. In some embodiments, the heteroarylcan be pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl. In someembodiments, R¹ can be chloro-substituted thienyl. In some embodiments,the heterocycloalkyl can be morpholinyl, oxanyl, or oxetanyl. In someembodiments, the fused ring aryl can be benzodioxinyl or naphthyl. Insome embodiments, R¹ can be substituted or unsubstituted phenyl. In someembodiments, L² can be a bond, and R² can be hydrogen. In someembodiments, L² can be substituted or unsubstituted alkylene or —C(O)—,and R² can be hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstituted fusedring aryl, or substituted or unsubstituted heteroaryl. In someembodiments, the heteroaryl can be pyridyl, pyridazinyl, pyrimidinyl,thienyl, or furyl. In some embodiments, R² can be substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocycloalkyl. In some embodiments, theheterocycloalkyl can be morpholinyl, oxanyl, or oxetanyl. In someembodiments, the fused ring aryl can be benzodioxinyl or naphthyl. Insome embodiments, R² can be substituted or unsubstituted phenyl. In someembodiments, the compound can be selected from those set forth in TableA.

Embodiments of the invention also encompass pharmaceutical compositionsincluding such compounds, or a compound as set forth in Table A, and apharmaceutically acceptable excipient. Embodiments of the invention alsoencompass methods for treating a disease or disorder in a subject,including administering such compounds or pharmaceutical compositions toa subject in need thereof in an amount effective to treat said diseaseor disorder. In some embodiments, the disease or disorder is athrombotic disorder. In some embodiments, the thrombotic disorder isacute coronary syndrome, venous thromboembolism, arterialthromboembolism or cardiogenic thromboembolism. In some embodiments, thedisease or disorder is fibrosis. In some embodiments, the disease ordisorder is Alzheimer's Disease. In some embodiments, the disease ordisorder is multiple sclerosis. In some embodiments, the disease ordisorder is pain. In some embodiments, the disease or disorder iscancer. Embodiments of the invention also encompass methods forpreventing a disease or disorder in a subject, including administeringsuch compounds or pharmaceutical compositions to a subject in needthereof in an amount effective to prevent said disease or disorder. Insome embodiments, the disease or disorder can be a thrombotic disorder.In some embodiments, the thrombotic disorder can be acute coronarysyndrome, venous thromboembolism, arterial thromboembolism orcardiogenic thromboembolism. In some embodiments, the thromboticdisorder can be disseminated intravascular coagulation. In someembodiments, the thrombotic disorder involves the presence or thepotential formation of a blood clot thrombus.

BRIEF DESCRIPTION OF THE DRAWINGS

Not applicable.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

As used herein, the term “attached” signifies a stable covalent bond,certain preferred points of attachment being apparent to those ofordinary skill in the art.

The terms “halogen” or “halo” include fluorine, chlorine, bromine, andiodine. Additionally, terms such as “haloalkyl” are meant to includemonohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedchain, or combination thereof, which can be fully saturated, mono- orpolyunsaturated and can include di- and multivalent radicals, having thenumber of carbon atoms designated (i.e., C₁-C₁₀ means one to tencarbons). Examples of saturated hydrocarbon radicals include, but arenot limited to, groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs andisomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and thelike. An unsaturated alkyl group is one having one or more double bondsor triple bonds. Examples of unsaturated alkyl groups include, but arenot limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and3-propynyl, 3-butynyl, and the higher homologs and isomers. Accordingly,the term “alkyl” can refer to C₁-C₁₆ straight chain saturated, C₁-C₁₆branched saturated, C₃-C₈ cyclic saturated and C₁-C₁₆ straight chain orbranched saturated aliphatic hydrocarbon groups substituted with C₃-C₈cyclic saturated aliphatic hydrocarbon groups having the specifiednumber of carbon atoms. For example, this definition shall include butis not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu),pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, isopropyl (i-Pr),isobutyl (i-Bu), tert-butyl (t-Bu), sec-butyl (s-Bu), isopentyl,neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclopropylmethyl, and the like.

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the compoundsdisclosed herein. A “lower alkyl” or “lower alkylene” is a shorter chainalkyl or alkylene group, generally having eight or fewer carbon atoms.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, consisting of at least one carbon atom and atleast one heteroatom selected from the group consisting of O, N, P, Si,and S, and wherein the nitrogen and sulfur atoms can optionally beoxidized, and the nitrogen heteroatom can optionally be quaternized. Theheteroatom(s) O, N, P, S, and Si can be placed at any interior positionof the heteroalkyl group or at the position at which the alkyl group isattached to the remainder of the molecule. Examples include, but are notlimited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and—CN. Up to two heteroatoms can be consecutive, such as, for example,—CH₂—NH—OCH₃.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl,and the like. Examples of heterocycloalkyl include, but are not limitedto, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively.

The term “alkenyl” includes C₂-C₁₆ straight chain unsaturated, C₂-C₁₁branched unsaturated, C₅-C₈ unsaturated cyclic, and C₂-C₁₆ straightchain or branched unsaturated aliphatic hydrocarbon groups substitutedwith C₃-C₈ cyclic saturated and unsaturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. Double bonds can occur inany stable point along the chain and the carbon-carbon double bonds canhave either the cis or trans configuration. For example, this definitionshall include but is not limited to ethenyl, propenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl,1,5-octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl,1-pentenyl-3-cyclohexenyl, and the like. Similarly, “heteroalkenyl”refers to heteroalkyl having one or more double bonds.

The term “alkynyl” refers in the customary sense to alkyl additionallyhaving one or more triple bonds. The term “cycloalkenyl” refers tocycloalkyl additionally having one or more double bonds. The term“heterocycloalkenyl” refers to heterocycloalkyl additionally having oneor more double bonds.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided herein.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″)═NR′″, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN, and —NO₂ in a number ranging fromzero to (2m′+1), where m′ is the total number of carbon atoms in suchradical. R′, R″, and R′″ each preferably independently refer tohydrogen, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl (e.g., aryl substituted with 1-3halogens), substituted or unsubstituted alkyl, alkoxy, or thioalkoxygroups, or arylalkyl groups. When a compound disclosed herein includesmore than one R group, for example, each of the R groups isindependently selected as are each R′, R″, and R′″ group when more thanone of these groups is present. When R′ and R″ are attached to the samenitrogen atom, they can be combined with the nitrogen atom to form a 4-,5-, 6-, or 7-membered ring. For example, —NR′R″ includes, but is notlimited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussionof substituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound togroups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NRSO₂R′, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂,fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a number ranging fromzero to the total number of open valences on the aromatic ring system;and where R′, R″, and R′″ are preferably independently selected fromhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl. When acompound disclosed herein includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, andR′″ groups when more than one of these groups is present.

Two or more substituents can optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringcan optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring can optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed can optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring can optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′— (C″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

The term “alkyloxy” (e.g. methoxy, ethoxy, propyloxy, allyloxy,cyclohexyloxy) represents an alkyl group as defined above having theindicated number of carbon atoms attached through an oxygen bridge(—O—).

The term “alkylthio” (e.g. methylthio, ethylthio, propylthio,cyclohexylthio and the like) represents an alkyl group as defined abovehaving the indicated number of carbon atoms attached through a sulfurbridge (—S—).

The term “alkylamino” represents one or two alkyl groups as definedabove having the indicated number of carbon atoms attached through anamine bridge. The two alkyl groups can be taken together with thenitrogen to which they are attached forming a cyclic system containing 3to 8 carbon atoms with or without one C₁-C₁₆alkyl, arylC₀-C₁₆alkyl, orC₀-C₁₆alkylaryl substituent.

The term “alkylaminoalkyl” represents an alkylamino group attachedthrough an alkyl group as defined above having the indicated number ofcarbon atoms.

The term “alkyloxy(alkyl)amino” (e.g. methoxy(methyl)amine,ethoxy(propyl)amine) represents an alkyloxy group as defined aboveattached through an amino group, the amino group itself having an alkylsubstituent.

The term “alkylcarbonyl” (e.g. cyclooctylcarbonyl, pentylcarbonyl,3-hexylcarbonyl) represents an alkyl group as defined above having theindicated number of carbon atoms attached through a carbonyl group.

The term “alkylcarboxy” (e.g. heptylcarboxy, cyclopropylcarboxy,3-pentenylcarboxy) represents an alkylcarbonyl group as defined abovewherein the carbonyl is in turn attached through an oxygen.

The term “alkylcarboxyalkyl” represents an alkylcarboxy group attachedthrough an alkyl group as defined above having the indicated number ofcarbon atoms.

The term “alkylcarbonylamino” (e.g. hexylcarbonylamino,cyclopentylcarbonylaminomethyl, methylcarbonylaminophenyl) represents analkylcarbonyl group as defined above wherein the carbonyl is in turnattached through the nitrogen atom of an amino group.

The nitrogen group can itself be substituted with an alkyl or arylgroup.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain from one to four heteroatoms selected from N, O, and S,wherein the nitrogen and sulfur atoms are optionally oxidized, and thenitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl”includes fused ring heteroaryl groups (i.e., multiple rings fusedtogether wherein at least one of the fused rings is a heteroaromaticring). A 5,6-fused ring heteroarylene refers to two rings fusedtogether, wherein one ring has 5 members and the other ring has 6members, and wherein at least one ring is a heteroaryl ring. Likewise, a6,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 6 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylenerefers to two rings fused together, wherein one ring has 6 members andthe other ring has 5 members, and wherein at least one ring is aheteroaryl ring. A heteroaryl group can be attached to the remainder ofthe molecule through a carbon or heteroatom. Non-limiting examples ofaryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below. An “arylene” and a“heteroarylene,” alone or as part of another substituent, mean adivalent radical derived from an aryl and heteroaryl, respectively.Accordingly, the term “aryl” can represent an unsubstituted, mono-, di-or trisubstituted monocyclic, polycyclic, biaryl and heterocyclicaromatic groups covalently attached at any ring position capable offorming a stable covalent bond, certain preferred points of attachmentbeing apparent to those skilled in the art (e. g. 3-indolyl,4-imidazolyl). The aryl substituents are independently selected from thegroup consisting of halo, nitro, cyano, trihalomethyl, arylC₁₋₁₆alkyl,C₀₋₁₆alkyloxyC₀₋₁₆alkyl, arylC₀₋₁₆alkyloxyC₀₋₁₆alkyl,C₀₋₁₆alkylthioC₀₋₁₆alkyl, arylC₀₋₁₆alkylthioC₀₋₁₆alkyl,C₀₋₁₆alkylaminoC₀₋₁₆alkyl, arylC₀₋₁₆alkylaminoC₀₋₁₆alkyl,di(arylC₁₋₁₆alkyl)aminoC₀₋₁₆alkyl, C₁₋₁₆alkylcarbonylC₀₋₁₆alkyl,arylC₁₋₁₆alkylcarbonylC₀₋₁₆alkyl, C₁₋₁₆alkylcarboxyC₀₋₁₆alkyl,arylC₁₋₁₆alkylcarboxyC₀₋₁₆alkyl, C₁₋₁₆alkylcarbonylaminoC₀₋₁₆alkyl,arylC₁₋₁₆alkylcarbonylaminoC₀₋₁₆alkyl, —C₀₋₁₆alkylCOOR₄,—C₀₋₁₆alkylCONR₅R₆ wherein R₄, R₅ and R₆ are independently selected fromhydrogen, C₁-C₁₁alkyl, arylC₀-C₁₁alkyl, or R₅ and R₆ are taken togetherwith the nitrogen to which they are attached forming a cyclic systemcontaining 3 to 8 carbon atoms with or without one C₁₋₁₆alkyl,arylC₀-C₁₆alkyl, or C₀-C₁₆alkylaryl substituent. Aryl includes but isnot limited to pyrazolyl and triazolyl.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the terms “arylalkyl,” “aralkyl” and thelike are meant to include those radicals in which an aryl group isattached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, andthe like) including those alkyl groups in which a carbon atom (e.g., amethylene group) has been replaced by, for example, an oxygen atom(e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, andthe like), or a sulfur atom. Accordingly, the terms “arylalkyl” and thelike (e.g. (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl,pyridylcyclopentyl) represents an aryl group as defined above attachedthrough an alkyl group as defined above having the indicated number ofcarbon atoms.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylsulfonyl,” as used herein, means a moiety having theformula —S(O₂)—R′, where R′ is an alkyl group as defined above. R′ canhave a specified number of carbons (e.g., “C₁-C₄ alkylsulfonyl”).

The term “carbonyloxy” represents a carbonyl group attached through anoxygen bridge.

In the above definitions, the terms “alkyl” and “alkenyl” can be usedinterchangeably in so far as a stable chemical entity is formed, aswould be apparent to those skilled in the art.

The term “linker” refers to attachment groups interposed betweensubstituents, e.g., R¹, R² or R³ described herein, e.g., Formula (Ia)and generically referred to as R^(n), and the group which issubstituted, e.g., “ring A” group of e.g., Formula (Ia). In someembodiments, the linker includes amido (—CONH—R^(n) or —NHCO—R^(n)),thioamido (—CSNH—R^(n) or —NHCS—R^(n)), carboxyl (—CO₂—R^(n) or—OCOR^(n)), carbonyl (—CO—R^(n)), urea (—NHCONH—R^(n)), thiourea(—NHCSNH—R^(n)), sulfonamido (—NHSO₂—R^(n) or —SO₂NH—R^(n)), ether(—O—R^(n)), sulfonyl (—SO₂—R^(n)), sulfoxyl (—SO—R^(n)), carbamoyl(—NHCO₂—R^(n) or —OCONH—R^(n)), or amino (—NHR^(n)) linking moieties.

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, oxo, halogen, —COOH,        unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted        cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,        unsubstituted heteroaryl, and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen, —COOH,            unsubstituted alkyl, unsubstituted heteroalkyl,            unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,            unsubstituted aryl, unsubstituted heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            and heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, halogen,                —COOH, unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, unsubstituted                heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, or heteroaryl, substituted with at least one                substituent selected from: oxo, —OH, —NH₂, —SH, —CN,                —CF₃, —NO₂, halogen, —COOH, unsubstituted alkyl,                unsubstituted heteroalkyl, unsubstituted cycloalkyl,                unsubstituted heterocycloalkyl, unsubstituted aryl, and                unsubstituted heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₄-C₈cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 4 to 8 membered heterocycloalkyl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₅-C₇ cycloalkyl, and each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7membered heterocycloalkyl.

The term “about” used in the context of a numeric value indicates arange of +/−10% of the numeric value, unless expressly indicatedotherwise.

II. Compounds

In one aspect, there is provided a compound with structure of Formula(Ia):

or pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.Ring A is substituted or unsubstituted pyrazolyl. L¹ and L³ areindependently a bond, substituted or unsubstituted alkylene, substitutedor unsubstituted heteroalkylene, —S—, —SO—, —SO₂—, —O—, —NHSO₂—, or—NR⁴—. L² is absent, a bond, a hydrogen, substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO₂—,—O—, —NHSO₂—, or —NR⁴—. R¹ and R³ are independently hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstituted fusedring aryl, or substituted or unsubstituted heteroaryl. R² is absent,hydrogen, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstituted fusedring aryl, or substituted or unsubstituted heteroaryl. R⁴ is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted heterocycloalkenyl, substituted orunsubstituted fused ring aryl, or substituted or unsubstitutedheteroaryl. Y is a halogen. In some embodiments, R² can be absentprovided L² is also absent.

In some embodiments, the compound is a pharmaceutically acceptable salt,ester, solvate, or prodrug of a compound of Formula (la). In someembodiments, the compound is not an ester, not a solvate, and not aprodrug.

Further to any embodiment above, in some embodiments L¹ is —S—, —NR⁴—,substituted or unsubstituted alkylene, or substituted or unsubstitutedheteroalkylene, where R⁴ is as described above in regards to formula Ia,and R¹ is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted fused ring aryl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedheterocycloalkyl. In some embodiments, R³ is substituted orunsubstituted aryl. In some embodiments, R³ is unsubstituted aryl. Insome embodiments, R³ is unsubstituted phenyl. In some embodiments, L² isa bond. In some embodiments, L² is a bond and R² is hydrogen. Y isfluorine.

Further to any embodiment above, in some embodiments L² is —C(O)—, andR² is substituted or unsubstituted alkyl, hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted fused ring aryl, or substituted orunsubstituted heteroaryl. In some embodiments, R² is unsubstituted aryl.In some embodiments, R² is unsubstituted phenyl.

In some embodiments, L² and R² are absent, providing a compound withstructure of Formula (Ib) following.

In some embodiments, the compound is a pharmaceutically acceptable salt,ester, solvate, or prodrug of a compound of Formula (Ib). In someembodiments, the compound is not an ester, not a solvate, and not aprodrug.

In some embodiments, there is provided a compound according to Formula(Ia) with structure of either of Formulae (IIa) or (IIb) following.

In some embodiments, the compound has the structure of Formula (IIa). Insome embodiments, L³ is a bond, or substituted or unsubstitutedalkylene, and R³ is substituted or unsubstituted aryl, substituted orunsubstituted fused ring aryl, substituted or unsubstitutedheterocycloalkyl, or substituted or unsubstituted heteroaryl. In someembodiments, R³ is substituted or unsubstituted phenyl, or substitutedor unsubstituted thienyl. In some embodiments, R³ is unsubstitutedphenyl. In some embodiments, R³ is unsubstituted thienyl. In someembodiments, R³ is a chloro-substituted thienyl. In some embodiments, R³is substituted or unsubstituted pyridyl, or substituted or unsubstitutedpyridazinyl. In some embodiments, R³ is unsubstituted pyridyl. In someembodiments, R³ is unsubstituted pyridazinyl. In some embodiments, R³ issubstituted or unsubstituted pyrimidinyl, or substituted orunsubstituted furyl. In some embodiments, R³ is unsubstitutedpyrimidinyl. In some embodiments, R³ is unsubstituted furyl. In someembodiments, R³ is substituted or unsubstituted morpholinyl, orsubstituted or unsubstituted oxanyl, or substituted or unsubstitutedoxetanyl. In some embodiments, R³ is unsubstituted morpholinyl. In someembodiments, R³ is unsubstituted oxanyl. In some embodiments, R³ isunsubstituted oxetanyl. In some embodiments, R³ is substituted orunsubstituted benzodioxinyl, or substituted or unsubstituted naphthyl.In some embodiments, R³ is unsubstituted benzodioxinyl. In someembodiments, R³ is unsubstituted naphthyl. In some embodiments, R³ issubstituted or unsubstituted phenyl. In some embodiments, Y is fluorine.

In some embodiments, the compound has the structure of Formula (IIa)wherein L³ is —C(O)O—, and R³ is substituted or unsubstituted alkyl, andY is fluorine.

In some embodiments, the compound has the structure of Formula (IIa)wherein L³ is —C(O)NR⁵—, R⁵ is hydrogen or alkyl, and R³ is substitutedor unsubstituted alkyl and Y is fluorine.

Further to any embodiment above wherein the compound has the structureof Formula (IIa), in some embodiments, L¹ is —S—, a bond, —NR⁴—,substituted or unsubstituted alkylene, or substituted or unsubstitutedheteroalkylene, where R⁴ is as described in formula Ia and R¹ ishydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted fused ring aryl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedheterocycloalkyl. In some embodiments, R¹ is a substituted orunsubstituted pyridyl. In some embodiments, R¹ is a substituted orunsubstituted pyridazinyl. In some embodiments, R¹ is a substituted orunsubstituted pyrimidinyl. In some embodiments, R¹ is a substituted orunsubstituted thienyl. In some embodiments, R¹ is a substituted orunsubstituted furyl. In some embodiments, R¹ is an unsubstitutedpyridyl. In some embodiments, R¹ is an unsubstituted pyridazinyl. Insome embodiments, R¹ is an unsubstituted pyrimidinyl. In someembodiments, R¹ is an unsubstituted thienyl. In some embodiments, R¹ isa chloro-substituted thienyl. In some embodiments, R¹ is anunsubstituted furyl. In some embodiments, R¹ is a substituted orunsubstituted morpholinyl. In some embodiments, R¹ is a substituted orunsubstituted oxanyl. In some embodiments, R¹ is a substituted orunsubstituted oxetanyl. In some embodiments, R¹ is an unsubstitutedmorpholinyl. In some embodiments, R¹ is an unsubstituted oxanyl. In someembodiments, R¹ is an unsubstituted oxetanyl. In some embodiments, R¹ issubstituted or unsubstituted benzodioxinyl. In some embodiments, R¹ issubstituted or unsubstituted naphthyl. In some embodiments, R¹ isunsubstituted benzodioxinyl. In some embodiments, R¹ is unsubstitutednaphthyl. In some embodiments, R¹ is substituted or unsubstitutedphenyl. In some embodiments, Y is fluorine.

Further to any embodiment above wherein the compound has the structureof Formula (IIa), in some embodiments, L² is a bond. In someembodiments, R² is hydrogen. In some embodiments, L² is substituted orunsubstituted alkylene or —C(O)—, and R² is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl,substituted or unsubstituted fused ring aryl, or substituted orunsubstituted heteroaryl. In some embodiments, R² is a substituted orunsubstituted pyridyl. In some embodiments, R² is a substituted orunsubstituted pyridazinyl. In some embodiments, R² is a substituted orunsubstituted pyrimidinyl. In some embodiments, R² is a substituted orunsubstituted thienyl. In some embodiments, R² is a substituted orunsubstituted furyl. In some embodiments, R² is an unsubstitutedpyridyl. In some embodiments, R² is an unsubstituted pyridazinyl. Insome embodiments, R² is an unsubstituted pyrimidinyl. In someembodiments, R² is an unsubstituted thienyl. In some embodiments, R² isa chloro-substituted thienyl. In some embodiments, R² is anunsubstituted furyl. In some embodiments, R² is a substituted orunsubstituted morpholinyl. In some embodiments, R² is a substituted orunsubstituted oxanyl. In some embodiments, R² is a substituted orunsubstituted oxetanyl. In some embodiments, R² is an unsubstitutedmorpholinyl. In some embodiments, R² is an unsubstituted oxanyl. In someembodiments, R² is an unsubstituted oxetanyl. In some embodiments, R² issubstituted or unsubstituted benzodioxinyl. In some embodiments, R² issubstituted or unsubstituted naphthyl. In some embodiments, R² isunsubstituted benzodioxinyl. In some embodiments, R² is unsubstitutednaphthyl. In some embodiments, R² is substituted or unsubstitutedphenyl. In some embodiments, Y is fluorine.

In some embodiments, the compound has the structure of Formula (IIb). Insome embodiments, L³ is a bond, or substituted or unsubstitutedalkylene, and R³ is substituted or unsubstituted aryl, substituted orunsubstituted fused ring aryl, substituted or unsubstitutedheterocycloalkyl, or substituted or unsubstituted heteroaryl. In someembodiments, R³ is substituted or unsubstituted phenyl, or substitutedor unsubstituted thienyl. In some embodiments, R³ is unsubstitutedphenyl. In some embodiments, R³ is unsubstituted thienyl. In someembodiments, R³ is a chloro-substituted thienyl. In some embodiments, R³is substituted or unsubstituted pyridyl, or substituted or unsubstitutedpyridazinyl. In some embodiments, R³ is unsubstituted pyridyl. In someembodiments, R³ is unsubstituted pyridazinyl. In some embodiments, R³ issubstituted or unsubstituted pyrimidinyl, or substituted orunsubstituted furyl. In some embodiments, R³ is unsubstitutedpyrimidinyl. In some embodiments, R³ is unsubstituted furyl. In someembodiments, R³ is substituted or unsubstituted morpholinyl, orsubstituted or unsubstituted oxanyl, or substituted or unsubstitutedoxetanyl. In some embodiments, R³ is unsubstituted morpholinyl. In someembodiments, R³ is unsubstituted oxanyl. In some embodiments, R³ isunsubstituted oxetanyl. In some embodiments, R³ is substituted orunsubstituted benzodioxinyl, or substituted or unsubstituted naphthyl.In some embodiments, R³ is unsubstituted benzodioxinyl. In someembodiments, R³ is unsubstituted naphthyl. In some embodiments, R³ issubstituted or unsubstituted phenyl. In some embodiments, Y is fluorine.

In some embodiments, the compound has the structure of Formula (IIb)wherein L³ is —C(O)O—, and R³ is substituted or unsubstituted alkyl, andY is fluorine.

In some embodiments, the compound has the structure of Formula (IIb)wherein L³ is —C(O)NR⁵—, R⁵ is hydrogen or alkyl, and R³ is substitutedor unsubstituted alkyl and Y is fluorine.

Further to any embodiment above wherein the compound has the structureof Formula (IIb), in some embodiments, L¹ is a bond, —S—, —NR⁴—,substituted or unsubstituted alkylene, or substituted or unsubstitutedheteroalkylene, where R⁴ is as described in formula Ia and R¹ ishydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted fused ring aryl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedheterocycloalkyl. In some embodiments, R¹ is a substituted orunsubstituted pyridyl. In some embodiments, R¹ is a substituted orunsubstituted pyridazinyl. In some embodiments, R¹ is a substituted orunsubstituted pyrimidinyl. In some embodiments, R¹ is a substituted orunsubstituted thienyl. In some embodiments, R¹ is a substituted orunsubstituted furyl. In some embodiments, R¹ is an unsubstitutedpyridyl. In some embodiments, R¹ is an unsubstituted pyridazinyl. Insome embodiments, R¹ is an unsubstituted pyrimidinyl. In someembodiments, R¹ is an unsubstituted thienyl. In some embodiments, R¹ isa chloro-substituted thienyl. In some embodiments, R¹ is anunsubstituted furyl. In some embodiments, R¹ is a substituted orunsubstituted morpholinyl. In some embodiments, R¹ is a substituted orunsubstituted oxanyl. In some embodiments, R¹ is a substituted orunsubstituted oxetanyl. In some embodiments, R¹ is an unsubstitutedmorpholinyl. In some embodiments, R¹ is an unsubstituted oxanyl. In someembodiments, R¹ is an unsubstituted oxetanyl. In some embodiments, R¹ issubstituted or unsubstituted benzodioxinyl. In some embodiments, R¹ issubstituted or unsubstituted naphthyl. In some embodiments, R¹ isunsubstituted benzodioxinyl. In some embodiments, R¹ is unsubstitutednaphthyl. In some embodiments, R¹ is substituted or unsubstitutedphenyl. In some embodiments, Y is fluorine.

Further to any embodiment above wherein the compound has the structureof Formula (IIb), in some embodiments, L² is a bond or substituted orunsubstituted alkylene. In some embodiments, L² is a bond. In someembodiments, L² is unsubstituted alkylene. In some embodiments, L² issubstituted alkylene. In some embodiments, R² is hydrogen. In someembodiments, R² is substituted or unsubstituted alkyl, or substituted orunsubstituted aryl. Further to any particular L², in some embodiments R²is substituted or unsubstituted alkyl, or substituted or unsubstitutedaryl. In some embodiments, R² is unsubstituted alkyl. In someembodiments, R² is unsubstituted aryl. In some embodiments, R³ isunsubstituted phenyl. In some embodiments, R² is substituted alkyl. Insome embodiments, R² is substituted aryl. In some embodiments, Y isfluorine.

Further to any embodiment above wherein the compound has the structureof Formula (IIb), in some embodiments, L² is substituted orunsubstituted alkylene or —C(O)—, and R² is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl,substituted or unsubstituted fused ring aryl, or substituted orunsubstituted heteroaryl. In some embodiments, R² is a substituted orunsubstituted pyridyl. In some embodiments, R² is a substituted orunsubstituted pyridazinyl. In some embodiments, R² is a substituted orunsubstituted pyrimidinyl. In some embodiments, R² is a substituted orunsubstituted thienyl. In some embodiments, R² is a substituted orunsubstituted furyl. In some embodiments, R² is an unsubstitutedpyridyl. In some embodiments, R² is an unsubstituted pyridazinyl. Insome embodiments, R² is an unsubstituted pyrimidinyl. In someembodiments, R² is an unsubstituted thienyl. In some embodiments, R² isa chloro-substituted thienyl. In some embodiments, R² is anunsubstituted furyl. In some embodiments, R² is a substituted orunsubstituted morpholinyl. In some embodiments, R² is a substituted orunsubstituted oxanyl. In some embodiments, R² is a substituted orunsubstituted oxetanyl. In some embodiments, R² is an unsubstitutedmorpholinyl. In some embodiments, R² is an unsubstituted oxanyl. In someembodiments, R² is an unsubstituted oxetanyl. In some embodiments, R² issubstituted or unsubstituted benzodioxinyl. In some embodiments, R² issubstituted or unsubstituted naphthyl. In some embodiments, R² isunsubstituted benzodioxinyl. In some embodiments, R² is unsubstitutednaphthyl. In some embodiments, R² is substituted or unsubstitutedphenyl. In some embodiments, Y is fluorine.

Exemplary compounds, e.g., multisubstituted aromatic compounds, inaccordance with the present disclosure are provided herein. In Table Afollowing, compound (Cmpd) number, chemical name (i.e., InternationalUnion of Pure and Applied Chemistry [IUPAC] name), molecular weight(MW_(calc) calculated mass) and biological activity (i.e., inhibitionactivity in a thrombin assay) are disclosed.

For Table A following, the disclosed compounds were assayed forinhibition of the protease activity of thrombin as described herein. InTable A, the level of inhibition in the thrombin assay is indicated asfollows: a: IC₅₀≤0.1 μM; b: 0.1 μM≤IC₅₀<1 μM; c: IC₅₀≥1 μM. Accordingly,in some embodiments, there is provided a compound as expressly set forthin Table A following.

TABLE A Cmpd Thrombin No. IUPAC Name MW Activity 11-(5-[(5-chlorothiophen-2-yl)methyl]amino-3-(1-[5- 648 a(dimethylamino)naphthalen-1-yl]sulfonylpiperidin-4-yl)-4-fluoro-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one 21-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-(5- 462 chydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 31-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-(oxan- 400 a4-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 41-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-(oxan- 416 a4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one 51-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-(oxan- 430 a4-yl)-1H-pyrazol-1-yl)-3-methoxy-2,2-dimethylpropan-1-one 61-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3- 399 a(piperidin-4-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 71-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3- 415 a(piperidin-4-yl)-1H-pyrazol-1-yl)-2-methoxy-2-methylpropan- 1-one 81-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3- 415 a(piperidin-4-yl)-1H-pyrazol-1-yl)-3-hydroxy-2,2- dimethylpropan-1-one 91-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3- 429 a(piperidin-4-yl)-1H-pyrazol-1-yl)-3-methoxy-2,2- dimethylpropan-1-one 101-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-phenyl- 392 a1H-pyrazol-1-yl)-2,2-dimethylpropan-1-one 111-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-phenyl- 394 a1H-pyrazol-1-yl)-2-hydroxy-2-methylpropan-1-one 121-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-phenyl- 408 a1H-pyrazol-1-yl)-2-methoxy-2-methylpropan-1-one 131-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-phenyl- 466 a1H-pyrazol-1-yl)-3-(2-methoxyethoxy)-2,2-dimethylpropan-1- one 141-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-phenyl- 408 a1H-pyrazol-1-yl)-3-hydroxy-2,2-dimethylpropan-1-one 151-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-phenyl- 422 a1H-pyrazol-1-yl)-3-methoxy-2,2-dimethylpropan-1-one 161-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 475 adimethylpropanoyl)-4-fluoro-1H-pyrazol-3- yl)phenyl]pyrrolidin-2-one 171-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,3-dihydro- 553 a1,4-benzodioxine-5-carbonyl)-4-fluoro-1H-pyrazol-3-yl)phenyl]pyrrolidin-2-one 181-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-1-(2- 540 cmethoxybenzoyl)-1H-pyrazol-3-yl)phenyl]-2,2,2- trifluoroethan-1-ol 191-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-1-(2- 525 amethoxybenzoyl)-1H-pyrazol-3-yl)phenyl]pyrrolidin-2-one 201-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-1- 485 c(furan-3-carbonyl)-1H-pyrazol-3-yl)phenyl]pyrrolidin-2-one 211-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-1H- 399 bpyrazol-3-yl)piperidine-1-carbonyl]cyclopropan-1-ol 221-[5-(benzylamino)-4-fluoro-3-(pyridin-2-yl)-1H-pyrazol-1-yl]- 352 a2,2-dimethylpropan-1-one 231-[5-(benzylamino)-4-fluoro-3-phenyl-1H-pyrazol-1-yl]-2,2- 351 adimethylpropan-1-one 241-benzoyl-N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-3- 420 a(oxan-4-yl)-1H-pyrazol-5-amine 251-benzoyl-N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-5- 420 c(oxan-4-yl)-1H-pyrazol-3-amine 262-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-phenyl- 661 b1H-pyrazole-1-carbonyl)phenyl 5- (dimethylamino)naphthalene-1-sulfonate27 4-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-phenyl- 661 c1H-pyrazole-1-carbonyl)phenyl 5- (dimethylamino)naphthalene-1-sulfonate28 4-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 491 adimethylpropanoyl)-4-fiuoro-1H-pyrazol-3- yl)phenyl]morpholin-3-one 296-(5-[(5-chlorothiophen-2-yl)methyl]amino-1-(2,2- 460 adimethylpropanoyl)-4-fluoro-1H-pyrazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-one 306-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fiuoro-1-(2- 512 cmethoxybenzoyl)-1H-pyrazol-3-yl)-1,2,3,4- tetrahydronaphthalen-1-ol 316-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-1-(2- 510 amethoxybenzoyl)-1H-pyrazol-3-yl)-1,2,3,4- tetrahydronaphthalen-1-one 32N-[(5-chlorothiophen-2-yl)methyl]-1-(2,3-dihydro-1,4- 478 abenzodioxine-5-carbonyl)-4-fluoro-3-(oxan-4-yl)-1H-pyrazol- 5-amine 33N-[(5-chlorothiophen-2-yl)methyl]-1-(2,3-dihydro-1,4- 477 abenzodioxine-5-carbonyl)-4-fluoro-3-(piperidin-4-yl)-1H- pyrazol-5-amine34 N-[(5-chlorothiophen-2-yl)methyl]-1-(2,3-dihydro-1,4- 470 abenzodioxine-5-carbonyl)-4-fluoro-3-phenyl-1H-pyrazol-5- amine 35N-[(5-chlorothiophen-2-yl)methyl]-1-(2,3-dihydro-1,4- 478 cbenzodioxine-5-carbonyl)-4-fluoro-5-(oxan-4-yl)-1H-pyrazol- 3-amine 36N-[(5-chlorothiophen-2-yl)methyl]-1-(2,4-dimethoxybenzoyl)- 480 a4-fluoro-3-(oxan-4-yl)-1H-pyrazol-5-amine 37N-[(5-chlorothiophen-2-yl)methyl]-1-(2,4-dimethoxybenzoyl)- 479 a4-fluoro-3-(piperidin-4-yl)-1H-pyrazol-5-amine 38N-[(5-chlorothiophen-2-yl)methyl]-1-(2,4-dimethoxybenzoyl)- 472 a4-fluoro-3-phenyl-1H-pyrazol-5-amine 39N-[(5-chlorothiophen-2-yl)methyl]-1-(2,4-dimethoxybenzoyl)- 480 c4-fluoro-5-(oxan-4-yl)-1H-pyrazol-3-amine 40N-[(5-chlorothiophen-2-yl)methyl]-3-(1-[5- 682 c(dimethylamino)naphthalen-1-yl]sulfonylpiperidin-4-yl)-4-fluoro-1-(2-methoxybenzoyl)-1H-pyrazol-5-amine 41N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(2- 450 amethoxybenzoyl)-3-(oxan-4-yl)-1H-pyrazol-5-amine 42N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(2- 449 amethoxybenzoyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine 43N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(2- 443 amethoxybenzoyl)-3-(pyridin-2-yl)-1H-pyrazol-5-amine 44N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(2- 442 amethoxybenzoyl)-3-phenyl-1H-pyrazol-5-amine 45N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(2- 450 cmethoxybenzoyl)-5-(oxan-4-yl)-1H-pyrazol-3-amine 46N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(3- 406 cmethyloxetane-3-carbonyl)-3-phenyl-1H-pyrazol-5-amine 47N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(4-methyloxane- 442 a4-carbonyl)-3-(oxan-4-yl)-1H-pyrazol-5-amine 48N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(4-methyloxane- 434 a4-carbonyl)-3-phenyl-1H-pyrazol-5-amine 49N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(furan-3- 410 acarbonyl)-3-(oxan-4-yl)-1H-pyrazol-5-amine 50N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(furan-3- 409 acarbonyl)-3-(piperidin-4-yl)-1H-pyrazol-5-amine 51N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-(furan-3- 402 acarbonyl)-3-phenyl-1H-pyrazol-5-amine 52N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-[4-(2- 494 amethoxyethoxy)benzoyl]-3-(oxan-4-yl)-1H-pyrazol-5-amine 53N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-1-[4-(morpholin-4- 505 ayl)benzoyl]-3-(oxan-4-yl)-1H-pyrazol-5-amine 54N-[(5-chlorothiophen-2-yl)methyl]-4-fluoro-3-(oxan-4-yl)-1- 426 a(thiophene-3-carbonyl)-1H-pyrazol-5-amine 55N-[(5-chlorothiophen-2-yl)methyl]-5-(1-[5- 682 c(dimethylamino)naphthalen-1-yl]sulfonylpiperidin-4-yl)-4-fluoro-1-(2-methoxybenzoyl)-1H-pyrazol-3-amine 56N-[(5-chlorothiophen-2-yl)methyl]-N-[4-fluoro-3-(5-oxo- 510 c5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazol-5-yl]-2- methoxybenzamide57 N-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3- 667 a(piperidin-4-yl)-1H-pyrazole-1-carbonyl)phenyl]-5-(dimethylamino)naphthalene-1-sulfonamide 58N-[4-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3- 660 aphenyl-1H-pyrazole-1-carbonyl)phenyl]-5-(dimethylamino)naphthalene-1-sulfonamide 59N-benzyl-4-fluoro-1-(2-methoxybenzoyl)-3-(pyridin-2-yl)-1H- 402 apyrazol-5-amine 60 N-benzyl-4-fluoro-1-(2-methoxybenzoyl)-3-phenyl-1H-401 a pyrazol-5-amine 61[1-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-(oxan- 414 a4-yl)-1H-pyrazole-1-carbonyl)cyclopropyl]methanol 62[1-(5-[(5-chlorothiophen-2-yl)methyl]amino-4-fluoro-3-phenyl- 406 a1H-pyrazole-1-carbonyl)cyclopropyl]methanol

Compounds disclosed herein also include racemic mixtures, stereoisomersand mixtures of the compounds, including isotopically-labeled andradio-labeled compounds. See e.g., Goding, 1986, MONOCLONAL ANTIBODIESPRINCIPLES AND PRACTICE; Academic Press, p. 104. Such isomers can beisolated by standard resolution techniques, including e.g., fractionalcrystallization, chiral chromatography, and the like. See e.g., Eliel,E. L. & Wilen S. H., 1993, STEREOCHEMISTRY IN ORGANIC COMPOUNDS; JohnWiley & Sons, New York.

In some embodiments, compounds disclosed herein have asymmetric centersand can occur as racemates, racemic mixtures, and as individualenantiomers or diastereoisomers, with all isomeric forms as well asmixtures thereof being contemplated for use in the compounds and methodsdescribed herein. The compounds contemplated for use in the compoundsand methods described herein do not include those that are known in theart to be too unstable to synthesize and/or isolate.

The compounds disclosed herein can also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds can be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations of the compoundsdisclosed herein, whether radioactive or not, are encompassed within thecontemplated scope.

In some embodiments, metabolites of the compounds disclosed herein areuseful for the methods disclosed herein.

In some embodiments, compounds contemplated herein are provided in theform of a prodrug. The term “prodrug” refers to a compound that can beconverted into a compound (e.g., a biologically active compound)described herein in vivo. Prodrugs can be useful for a variety of reasonknown in the art, including e.g., ease of administration due e.g., toenhanced bioavailable in oral administration, and the like. The prodrugcan also have improved solubility in pharmaceutical compositions overthe biologically active compounds. An example, without limitation, of aprodrug is a compound which is administered as an ester (i.e., the“prodrug”) to facilitate transmittal across a cell membrane where watersolubility is detrimental to mobility but which then is metabolicallyhydrolyzed to the carboxylic acid, the active entity, once inside thecell where water-solubility is beneficial. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in DESIGN OF PRODRUGS, (ed. H. Bundgaard,Elsevier, 1985), which is hereby incorporated herein by reference forthe limited purpose describing procedures and preparation of suitableprodrug derivatives.

Accordingly, in some embodiments, compounds contemplated herein areprovided in the form of a prodrug ester. The term “prodrug ester” refersto derivatives of the compounds disclosed herein formed by the additionof any of a variety of ester-forming groups, e.g., groups known in theart, that are hydrolyzed under physiological conditions. Examples ofprodrug ester groups include pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, as well as other such groupsknown in the art, including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group.Other examples of prodrug ester groups can be found in, for example, T.Higuchi and V. Stella, in “Pro-drugs as Novel Delivery Systems”, Vol.14, A.C.S. Symposium Series, American Chemical Society (1975); andBIOREVERSIBLE CARRIERS IN DRUG DESIGN: THEORY AND APPLICATION, edited byE. B. Roche, Pergamon Press: New York, 14-21 (1987) (providing examplesof esters useful as prodrugs for compounds containing carboxyl groups).Each of the above-mentioned references is herein incorporated byreference for the limited purpose of disclosing ester-forming groupsthat can form prodrug esters.

In some embodiments, prodrugs can be slowly converted to the compoundsdescribed herein useful for the methods described herein when placed ina transdermal patch reservoir with a suitable enzyme or chemicalreagent.

Certain compounds disclosed herein can exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of contemplated compounds. Certain compounds of the presentinvention can exist in multiple crystalline or amorphous forms. Ingeneral, all physical forms are equivalent for the compounds and methodscontemplated herein and are intended to be within the scope disclosedherein.

III. Biological Activities

In some embodiments, compounds described herein exhibit inhibitoryactivity against thrombin with activities ≥1 μM, e.g., about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32,34, 36, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 μM, oreven greater. In some embodiments, the compounds exhibit inhibitoryactivity against thrombin with activities between 0.1 μM and 1 μM, e.g.,about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 μM. In someembodiments, compounds described herein exhibit inhibitory activityagainst thrombin with activities ≤0.1 μM, e.g., about 1, 2, 5, 10, 15,20, 30, 40, 50, 60, 70, 80, 90, or 100 nM. Ranges of values using acombination of any of the values recited herein as upper and/or lowerlimits are also contemplated, for example, but not limited to, 1-10 nM,10-100 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200 μM, 200-500 μM, or even500-1000 μM. In some embodiments, the inhibitory activity is in therange of about 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10 μM, 10-100 μM, 100-200μM, 200-500 μM, or even 500-1000 μM. It is understood that for purposesof quantification, the terms “activity,” “inhibitory activity,”“biological activity,” “thrombin activity” and the like in the contextof an inhibitory compound disclosed herein can be quantified in avariety of ways known in the art. Unless indicated otherwise, as usedherein such terms refer to IC₅₀ in the customary sense (i.e.,concentration to achieve half-maximal inhibition).

Inhibitory activity against thrombin in turn inhibits the bloodcoagulation process. Accordingly, compounds disclosed herein areindicated in the treatment or management of thrombotic disorders. Insome embodiments, a dose or a therapeutically effective dose of acompound disclosed herein will be that which is sufficient to achieve aplasma concentration of the compound or its active metabolite(s) withina range set forth herein, e.g., about 1-10 nM, 10-100 nM, 0.1-1 μM, 1-10μM, 10-100 μM, 100-200 μM, 200-500 μM, or even 500-1000 μM, preferablyabout 1-10 nM, 10-100 nM, or 0.1-1 μM. Without wishing to be bound byany theory, it is believe that such compounds are indicated in thetreatment or management of thrombotic disorders.

IV. Methods of Treating and Preventing Disease

Thrombosis.

Thrombotic diseases are the primary indications for thrombin inhibition,because of thrombin's location in the coagulation cascade and, in turn,the importance of the coagulation cascade in the progression of bloodclotting processes. However, without wishing to be bound by any theory,it is believed the coagulation cascade in general, and thrombin inparticular, is important in a variety other disease states.

It has been discovered that compounds described herein, e.g.,multisubstituted aromatic compounds, exhibit inhibitory action againstthrombin (activated blood-coagulation factor II; EC 3.4.21.5). This, inturn inhibits the blood coagulation process.

This inhibitory action is useful in the treatment of a variety ofthrombotic disorders, such as, but not limited to, acute vasculardiseases such as acute coronary syndromes; venous-, arterial- andcardiogenic thromboembolisms; the prevention of other states such asdisseminated intravascular coagulation, or other conditions that involvethe presence or the potential formation of a blood clot thrombus. Otherindications for methods described herein include the following.

Cancer.

It has long been recognized that cancer progression is accompanied byvenous thrombosis, but it has not been understood how each disease isrelated. From several clinical trials studying the treatment of VTE,metaanalyses have shown that low molecular weight heparins (LMWHs)improve overall survival in subgroups of cancer patients. See e.g.,Zacharski, L. R. & Lee, A. Y., 2008, Expert Opin Investig Drugs,17:1029-1037; Falanga, A. & Piccioli, A., 2005, Current Opinion inPulmonary Medicine, 11:403-407; Smorenburg, S. M., et al., 1999, ThrombHaemost, 82:1600-1604; Hettiarachchi, R. J., et al., 1999, ThrombHaemost, 82:947-952. This finding was substantiated in later clinicaltrials that measured specifically the survival of cancer patients. Seee.g., Lee, A. Y. et al., 2005, J Clin Oncol, 23:2123-2129; Klerk, C. P.et al., J Clin Oncol 2005, 23:2130-2135; Kakkar, A. K., et al., 2004, JClin Oncol, 22:1944-1948; Altinbas, M., et al., 2004, J Thromb Haemost,2:1266-1271.

More recently, researchers have focused on the specific anticancereffect of DTIs. For example, it was shown that heparin significantlyprolonged the survival of patients with limited small cell lung cancer.See e.g., Akl, E. A., et al., 2008, J Exp Clin Cancer Res, 27:4. Otherinvestigators found that systemic use of argatroban reduced tumor massand prolonged survival time in rat glioma models leading to theconclusion that argatroban should be considered as a novel therapeuticfor glioma, a notoriously difficult to treat cancer type. See e.g., Hua,Y., et al., 2005, Acta Neurochir, Suppl 2005, 95:403-406; Hua, Y., etal., 2005, J Thromb Haemost, 3:1917-1923. Very recently, it wasdemonstrated that dabigatran etexilate, a DTI recently FDA-approved (seee.g., Hughes, B., 2010, Nat Rev Drug Discov, 9:903-906) for DVTindications, inhibited both the invasion and metastasis of malignantbreast tumors. See e.g., DeFeo, K. et al., 2010, Thrombosis Research,125 (Supplement 2): S188-S188; Defeo, K., et al., 2010, Cancer BiolTher, 10:1001-1008. Thus, dabigatran etexilate treatment led to a 50%reduction in tumor volume at 4 weeks with no weight loss in treatedmice. Dabigatran etexilate also reduced tumor cells in the blood andliver micrometastases by 50-60%. These investigators concluded thatdabigatran etexilate can be beneficial in not only preventing thromboticevents in cancer patients, but also as adjunct therapy to treatmalignant tumors.

Further, hirudin and the LMWH nadroparin dramatically reduced the numberof lung metastases when administered prior to cancer cell inoculation.See e.g., Hu, L., et al., 2004, Blood, 104:2746-51.

The de novo thrombin inhibitor d-Arg-Oic-Pro-d-Ala-Phe(p-Me) has beenfound to block thrombin-stimulated invasion of prostate cancer cell linePC-3 in a concentration dependent manner. See e.g., Nieman, M. T., etal., 2008, J Thromb Haemost, 6:837-845. A reduced rate of tumor growthwas observed in mice dosed with the pentapeptide through their drinkingwater. The mice also showed reduced fold rate in tumor size and reducedoverall tumor weight compared to untreated mice. Microscopic examinationof treated tumors showed reduced number of large blood vessels thusconcluding that the pentapeptide interfered with tumor angiogenesis.Nieman, M. T., et al., Thromb Haemost, 104:1044-8.

In view of these and related studies, it is suggested thatanticoagulants affect tumor metastasis; that is, angiogenesis, cancercell adhesion, migration and invasion processes. See e.g., Van Noorden,C. J., et al., 2010, Thromb Res, 125 Suppl 2:S77-79.

Fibrosis.

Several studies have shown the utility of anticoagulant therapy infibrotic disorders. For example, in a rat model of CCl₄-induced chronicliver injury, the DTI SSR182289 decreased liver fibrogenesissignificantly after 7 weeks of administration. Similar observations weremade in other studies using the LMWHs nadroparin, tinzaparin,enoxaparin, and dalteparin sodium. See e.g., Duplantier, J. G., et al.,2004, Gut, 53:1682-1687; Abdel-Salam, O. M., et al., 2005, PharmacolRes, 51:59-67; Assy, N., et al., 2007, Dig Dis Sci, 52:1187-1193; Abe,W., et al., 2007, J Hepatol, 46:286-294.

In another example, the DTI melagatran greatly reduced ischemiareperfusion injury in a kidney transplant model in the large white pig.This led to a drastically improved kidney graft survival at 3 months.See e.g., Favreau, F., et al., 2010, Am J Transplant, 10:30-39.

Recent studies have shown that in a bleomycin-induced mouse model ofpulmonary fibrosis, dabigatran etexilate treatment reduced importantprofibrotic events in lung fibroblasts, including the production ofcollagen and connective tissue growth factor. See e.g., Silver, R. M.,et al., 2010, Am. J Respir. Crit. Care Med., 181:A6780; Bogatkevich, G.S., et al., 2009, Arthritis Rheum, 60:3455-3464.

The above experimental evidence points to a close relationship betweenthrombin and fibrosis and suggests novel therapeutic opportunities forfibrosis using thrombin inhibitors. See e.g., Calvaruso, V., et al.,2008, Gut, 57:1722-1727; Chambers, R. C., 2008, Br J Pharmacol, 153Suppl 1:S367-378; Chambers, R. C. & Laurent, G. J., 2002, Biochem SocTrans, 30:194-200; Howell, D. C., et al., 2001, Am J Pathol,159:1383-1395.

Alzheimer's Disease.

Very recent experiments confirm higher thrombin levels in brainendothelial cells of patients with Alzheimer's disease. While ‘normal’thrombin levels are connected to regulatory CNS functions, thrombinaccumulation in the brain is toxic. It has also been found that theneural thrombin inhibitor Protease Nexin 1 (PN-1) is significantlyreduced in the Alzheimer's disease brain, despite the fact that PN-1mRNA levels are unchanged. These observations have led someinvestigators to suggest that reduction of CNS-resident thrombin willprove useful in Alzheimer's Disease (AD) treatment. See e.g., Vaughan,P. J., et al., 1994, Brain Res, 668:160-170; Yin, X., et al., 2010, Am JPathol, 176:1600-1606; Akiyama, H., et al., 1992, Neurosci Lett,146:152-154.

Multiple Sclerosis.

Investigators found that hirudin treatment in an animal model ofMultiple Sclerosis (MS) showed a dramatic improvement in diseaseseverity. See e.g., Han, M. H., et al., 2008, Nature, 451:1076-1081.Similar results were obtained following treatment with heparin (a DTI)and dermatan sulfate another coagulation inhibitor. See e.g.,Chelmicka-Szorc, E. & Amason, B. G., 1972, Arch Neurol, 27:153-158;Inaba, Y., et al., 1999, Cell Immunol, 198:96-102. Other evidence showsthat naturally occurring antithrombin III has anti-inflammatory effectsin diseases such as endotoxemia and other sepsis-related conditions. Seee.g., Wiedermann, C. J. & Romisch, J., 2002, Acta Med Austriaca,29:89-92. Naturally occurring thrombin inhibitors are presumablysynthesized in situ and have protective roles in CNS inflammation.Therefore, therapeutic thrombin inhibition has been proposed as apotential MS treatment. See e.g., Luo, W., et al., 2009, In: THROMBIN,Maragoudakis, M. E.; Tsopanoglou, N. E., Eds. Springer New York: 2009;pp 133-159.

Pain.

In a rat pain model with partial lesion of the sciatic nerve,intrathecal hirudin prevented the development of neuropathic pain andcurbed pain responses for 7 days. The investigators found that followinginjury, neuropathic pain was mediated by thrombin generation, which inturn activated PAR-1 receptor in the spinal cord. Hirudin inhibitedthrombin generation and ultimately led to pain relief. See e.g., Garcia,P. S., et al., 2010, Thromb Haemost, 103:1145-1151; Narita, M., et al.,2005, J Neurosci, 25:10000-10009. Researchers hypothesize that thrombinand the PARs are involved not just as part of the coagulation cascade,but in inflammation, nociception and neurodevelopment. Development of aDTI to intersect an unexploited pharmacology will lead to paintherapeutics distinct from opioids and NSAIDs, whose shortcomings arewell documented. See e.g., Garcia 2010, Id.

Accordingly, in a further aspect, there is provided a method fortreating a disease or disorder in a subject in need thereof. The methodincludes administering a compound of any of Formulae (Ia), (Ib), (IIa)or (IIb) as disclosed herein, a compound as set forth in Table A,pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, orpharmaceutical composition thereof, to a subject in need thereof in anamount effective to treat the disease or disorder. The terms“therapeutically effective amount,” “amount effective to treat,” “amounteffective to prevent” and the like refer to that amount of drug orpharmaceutical agent (e.g., compound or pharmaceutical compositiondisclosed herein) that will elicit the biological or medical response ofa tissue, system, animal, or human that is being sought by a researcher,veterinarian, medical doctor or other clinician.

In some embodiments, the disease or disorder is a thrombotic disease ordisorder. In some embodiments, the thrombotic disease or disorder isacute coronary syndrome, venous thromboembolism, arterialthromboembolism or cardiogenic thromboembolism. In some embodiments, thethrombotic disease or disorder is acute coronary syndrome. In someembodiments, the thrombotic disease or disorder is venousthromboembolism. In some embodiments, the thrombotic disease or disorderis arterial thromboembolism. In some embodiments, the thrombotic diseaseor disorder is cardiogenic thromboembolism.

In some embodiments, the disease or disorder is fibrosis, Alzheimer'sDisease, multiple sclerosis, pain, or cancer. In some embodiments, thedisease or disorder is Alzheimer's Disease. In some embodiments, thedisease or disorder is multiple sclerosis.

In some embodiments, the disease or disorder is fibrosis. In someembodiments contemplating fibrosis, the method is directed to treatingchronic liver injury. In some embodiments, the disease or disorder isischemia reperfusion injury. In some embodiments, the disease ordisorder is pulmonary fibrosis.

In some embodiments, the disease or disorder is pain. In someembodiments, the pain is neuropathic pain.

In some embodiments, the disease or disorder is cancer. In someembodiments, the cancer is limited small cell lung cancer. In someembodiments, the cancer is a glioma. In some embodiments, the cancer ismalignant breast cancer. In some embodiments, the cancer is amicrometastasis. In some embodiments, the micrometastasis is of theblood or liver. In some embodiments, the cancer is a lung metastasis. Insome embodiments, the cancer is prostatic cancer.

In another aspect, there is provided a method for preventing a diseaseor disorder in a subject. The method includes administering a compoundof any of Formulae (Ia), (Ib), (IIa) or (IIb) as disclosed herein,compound as set forth in Table A herein, pharmaceutically acceptablesalt, ester, solvate, or prodrug thereof, or pharmaceutical compositionthereof, to a subject in need thereof in an amount effective to preventthe disease or disorder.

In some embodiments, the disease or disorder is a thrombotic disorder.In some embodiments, the thrombotic disorder is acute coronary syndrome,venous thromboembolism, arterial thromboembolism or cardiogenicthromboembolism. In some embodiments, the thrombotic disease or disorderis disseminated intravascular coagulation. In some embodiments, thethrombotic disorder involves the presence or the potential formation ofa blood clot thrombus.

Yet further to this aspect, in some embodiments, the disease or disorderis fibrosis, Alzheimer's Disease, multiple sclerosis, pain, or cancer.In some embodiments, the disease or disorder is fibrosis. In someembodiments, the disease or disorder is Alzheimer's Disease. In someembodiments, the disease or disorder is multiple sclerosis. In someembodiments, the disease or disorder is pain. In some embodiments, thedisease or disorder is cancer.

V. Assays

Compounds described herein can be assayed, by a variety of methods knownin the art and described herein, for inhibition of biological activity,e.g., protease activity, of a variety of proteins, e.g., thrombin. Forexample, the protease activity of such proteins, e.g., thrombin, can bemonitored using a chromophoric substrate, e.g., a p-nitroanilide peptidesubstrate, which upon hydrolysis releases p-nitroanilide, which in turngives rise to a color change which can be determinedspectrophotometrically. See e.g., Lottenberg, R, et al., 1983,Biochemica et Biophysica Acta, 752:539-557. Accordingly, the change incolor can be monitored with a spectrophotometer at e.g., 405 nm toprovide a signal which is directly proportional to the proteolyticactivity of the enzyme.

The thrombin activity reported herein (e.g., Table A) was obtained asfollows. Human thrombin was obtained from Haematologic Technologies Inc.The chromogenic substrate S-2238 was obtained from DiaPharma. Thrombinwas assayed in buffer containing 0.05 M Tris (pH 7.4), 0.015 M NaCl and0.01% PEG-8000. The final concentration of enzyme used was 3 nMthrombin. The final concentration of substrate used was 125 μM S-2238for thrombin. All assays were performed in 96-well microtiter plates atroom temperature (RT). The enzyme and inhibitor were pre-incubated for10 minutes then substrate was added and read at 405 nm in a SpectraMaxPlus Spectrophotometer (Molecular Devices). Inhibitor IC₅₀ values weredetermined by adding test compound as ten point, three-fold serialdilutions in buffer solution, as known in the art. The plate was read at10 minutes after substrate addition. The IC₅₀ was calculated by plottingthe percent (%) inhibition against compound concentration and fittingthe data to a constrained four parameter sigmoidal curve, as known inthe art.

VI. Pharmaceutical Compositions

In another aspect, there is provided a pharmaceutical compositioncomprising a compound disclosed herein and a pharmaceutically acceptableexcipient. The compound is a compound of any of Formulae (Ia), (Ib),(IIa) or (IIb) as disclosed herein, a compound as set forth in Table Aherein, or pharmaceutically acceptable salt, ester, solvate, or prodrugthereof. In some embodiments, the compound is set forth in Table Aherein.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds disclosed herein containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts includesodium, potassium, calcium, ammonium, organic amino, or magnesium salt,or a similar salt. When compounds disclosed herein contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like (see, for example, Bergeet al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977,66, 1-19). Certain specific compounds disclosed herein contain bothbasic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts.

Compounds disclosed herein can exist as salts, such as withpharmaceutically acceptable acids. Accordingly, the compoundscontemplated herein include such salts. Examples of such salts includehydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts can be prepared by methods known to those skilled in theart.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

Pharmaceutically acceptable salts of the compounds above, where a basicor acidic group is present in the structure, are also included withinthe scope of compounds contemplated herein. When an acidic substituentis present, such as —NHSO₃H, —COOH and —P(O)(OH)₂, there can be formedthe ammonium, sodium, potassium, calcium salt, and the like, for use asthe dosage form. Basic groups, such as amino or basic heteroarylradicals, or pyridyl and acidic salts, such as hydrochloride,hydrobromide, acetate, maleate, palmoate, methanesulfonate,p-toluenesulfonate, and the like, can be used as the dosage form.

Also, in the embodiments in which R—COOH is present, pharmaceuticallyacceptable esters can be employed, e. g., methyl, ethyl, tert-butyl,pivaloyloxymethyl, and the like, and those esters known in the art formodifying solubility or hydrolysis characteristics for use as sustainedrelease or prodrug formulations.

A. Formulations

The compounds disclosed herein can be prepared and administered in awide variety of oral, parenteral, and topical dosage forms. Thus, thecompounds can be administered by injection (e.g. intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally, orintraperitoneally). Also, the compounds described herein can beadministered by inhalation, for example, intranasally. Additionally, thecompounds disclosed herein can be administered transdermally. It is alsoenvisioned that multiple routes of administration (e.g., intramuscular,oral, transdermal) can be used to administer the compounds disclosedherein. In some embodiments, the compounds disclosed herein can beadministered orally as tablets, aqueous or oily suspensions, lozenges,troches, powders, granules, emulsions, capsules, syrups or elixirs. Thecomposition for oral use can contain one or more agents selected fromthe group of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to produce pharmaceutically elegant andpalatable preparations. Accordingly, there are also providedpharmaceutical compositions comprising a pharmaceutically acceptablecarrier or excipient and one or more compounds disclosed herein.

In some embodiments, tablets contain the acting ingredient in admixturewith non-toxic pharmaceutically acceptable excipients that are suitablefor the manufacture of tablets. These excipients can be, for example,(1) inert diluents, such as calcium carbonate, lactose, calciumphosphate, carboxymethylcellulose, or sodium phosphate; (2) granulatingand disintegrating agents, such as corn starch or alginic acid; (3)binding agents, such as starch, gelatin or acacia; and (4) lubricatingagents, such as magnesium stearate, stearic acid or talc. These tabletscan be uncoated or coated by known techniques to delay disintegrationand absorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate can beemployed.

For preparing pharmaceutical compositions from the compounds disclosedherein, pharmaceutically acceptable carriers can be either solid orliquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier can be one or more substance that can also act as diluents,flavoring agents, binders, preservatives, tablet disintegrating agents,or an encapsulating material.

A compound disclosed herein, in the form of a free compound or apharmaceutically-acceptable pro-drug, metabolite, analogue, derivative,solvate or salt, can be administered, for in vivo application,parenterally by injection or by gradual perfusion over time.Administration can be intravenously, intraperitoneally, intramuscularly,subcutaneously, intracavity, or transdermally. For in vitro studies thecompounds can be added or dissolved in an appropriate biologicallyacceptable buffer and added to a cell or tissue.

In powders, the carrier is a finely divided solid in a mixture with thefinely divided active component. In tablets, the active component ismixed with the carrier having the necessary binding properties insuitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from 5% to 70% of the activecompound. Suitable carriers are magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoabutter, and the like. The term “preparation” is intended to include theformulation of the active compound with encapsulating material as acarrier providing a capsule in which the active component with orwithout other carriers, is surrounded by a carrier, which is thus inassociation with it. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used assolid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

When parenteral application is needed or desired, particularly suitableadmixtures for the compounds disclosed herein are injectable, sterilesolutions, preferably oily or aqueous solutions, as well as suspensions,emulsions, or implants, including suppositories. In particular, carriersfor parenteral administration include aqueous solutions of dextrose,saline, pure water, ethanol, glycerol, propylene glycol, peanut oil,sesame oil, polyoxyethylene-block polymers, and the like. Ampoules areconvenient unit dosages. The compounds disclosed herein can also beincorporated into liposomes or administered via transdermal pumps orpatches. Pharmaceutical admixtures suitable for use in thepharmaceuticals compositions and methods disclosed herein include thosedescribed, for example, in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub.Co., Easton, Pa.) and WO 96/05309, the teachings of both of which arehereby incorporated by reference.

In some embodiments, preparations for parenteral administration includesterile aqueous or non-aqueous solutions, suspensions, and emulsions.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, vegetable oils such as olive oil, and injectable organic esterssuch as ethyl oleate. Aqueous carriers include water, alcoholic/aqueoussolutions, emulsions or suspensions, including saline and bufferedmedia. Parenteral vehicles include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's intravenousvehicles include fluid and nutrient replenishers, electrolytereplenishers (such as those based on Ringer's dextrose), and the like.Preservatives and other additives can also be present such as, forexample, antimicrobials, anti-oxidants, chelating agents, growth factorsand inert gases and the like.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations can contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation can bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

Some compounds can have limited solubility in water and therefore canrequire a surfactant or other appropriate co-solvent in the composition.Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68,F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Suchco-solvents are typically employed at a level between about 0.01% andabout 2% by weight.

Viscosity greater than that of simple aqueous solutions can be desirableto decrease variability in dispensing the formulations, to decreasephysical separation of components of a suspension or emulsion offormulation, and/or otherwise to improve the formulation. Such viscositybuilding agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propylcellulose, chondroitin sulfate and salts thereof, hyaluronic acid andsalts thereof, and combinations of the foregoing. Such agents aretypically employed at a level between about 0.01% and about 2% byweight.

The compositions disclosed herein can additionally include components toprovide sustained release and/or comfort. Such components include highmolecular weight, anionic mucomimetic polymers, gelling polysaccharides,and finely-divided drug carrier substrates. These components arediscussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841;5,212,162; and 4,861,760. The entire contents of these patents areincorporated herein by reference in their entirety for all purposes.

By the present, there are provided methods for ameliorating woundhealing and for mediating tissue repair (including but not limited totreatment of peripheral and coronary vascular disease). According tothese methods, a subject having a wound or in need of tissue repair, istreated at the site of the wound or damaged tissue or treatedsystemically, with a compound disclosed herein in the form of a freecompound or a pharmaceutically-acceptable prodrug, metabolite, analogue,derivative, solvate or salt.

Generally, the terms “treating”, “treatment” and the like are usedherein to mean affecting a subject, tissue or cell to obtain a desiredpharmacologic and/or physiologic effect. The effect can be prophylacticin terms of completely or partially preventing a disease or disorder orsign or symptom thereof, and/or can be therapeutic in terms of a partialor complete cure for a disorder and/or adverse effect attributable toit. “Treating” as used herein covers any treatment of, or prevention ofa disease or disorder in a vertebrate, a mammal, particularly a human,and includes: (a) preventing the disease or disorder from occurring in asubject that can be predisposed to the disease or disorder, but has notyet been diagnosed as having it; (b) inhibiting the disease or disorder,i. e., arresting its development; or (c) relieving or ameliorating thedisease or disorder, i. e., cause regression of the disease or disorder.

There are provided various pharmaceutical compositions useful forameliorating diseases and disorders, including thrombosis. In someembodiments, the disease or disorder is a thrombotic disorder. In someembodiments, the disease or disorder is acute coronary syndrome, venousthromboembolism, arterial thromboembolism or cardiogenicthromboembolism. In some embodiments, the disease or disorder isfibrosis. In some embodiments, the disease or disorder is Alzheimer'sDisease. In some embodiments, the disease or disorder is multiplesclerosis. In some embodiments, the disease or disorder is pain. In someembodiments, the disease or disorder is cancer. The pharmaceuticalcompositions according to one embodiment are prepared by formulating acompound disclosed herein in the form of a free compound or apharmaceutically-acceptable pro-drug, metabolite, analogue, derivative,solvate or salt, either alone or together with other pharmaceuticalagents, suitable for administration to a subject using carriers,excipients and additives or auxiliaries. Frequently used carriers orauxiliaries include magnesium carbonate, titanium dioxide, lactose,mannitol and other sugars, talc, milk protein, gelatin, starch,vitamins, cellulose and its derivatives, animal and vegetable oils,polyethylene glycols and solvents, such as sterile water, alcohols,glycerol and polyhydric alcohols. Intravenous vehicles include fluid andnutrient replenishers.

Preservatives include antimicrobial, anti-oxidants, chelating agents andinert gases. Other pharmaceutically acceptable carriers include aqueoussolutions, non-toxic excipients, including salts, preservatives, buffersand the like, as described, for instance, in Remington's PharmaceuticalSciences, 15th ed. Easton: Mack Publishing Co., 1405-1412, 1461-1487(1975) and The National Formulary XIV., 14th ed. Washington: AmericanPharmaceutical Association (1975), the contents of which are herebyincorporated by reference. The pH and exact concentration of the variouscomponents of the pharmaceutical composition are adjusted according toroutine skills in the art. See e.g., Goodman and Gilman (eds.), 1990,THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.).

The pharmaceutical compositions are preferably prepared and administeredin dose units. Solid dose units are tablets, capsules and suppositories.For treatment of a subject, depending on activity of the compound,manner of administration, nature and severity of the disease ordisorder, age and body weight of the subject, different daily doses canbe used.

Under certain circumstances, however, higher or lower daily doses can beappropriate. The administration of the daily dose can be carried outboth by single administration in the form of an individual dose unit orelse several smaller dose units and also by multiple administrations ofsubdivided doses at specific intervals.

The pharmaceutical compositions contemplated herein can be administeredlocally or systemically in a therapeutically effective dose. Amountseffective for this use will, of course, depend on the severity of thedisease or disorder and the weight and general state of the subject.Typically, dosages used in vitro can provide useful guidance in theamounts useful for in situ administration of the pharmaceuticalcomposition, and animal models can be used to determine effectivedosages for treatment of particular disorders.

Various considerations are described, e. g., in Langer, 1990, Science,249: 1527; Goodman and Gilman's (eds.), 1990, Id., each of which isherein incorporated by reference and for all purposes. Dosages forparenteral administration of active pharmaceutical agents can beconverted into corresponding dosages for oral administration bymultiplying parenteral dosages by appropriate conversion factors. As togeneral applications, the parenteral dosage in mg/m2 times 1.8=thecorresponding oral dosage in milligrams (“mg”). As to oncologyapplications, the parenteral dosage in mg/m2 times 1.6=the correspondingoral dosage in mg. An average adult weighs about 70 kg. See e.g.,Miller-Keane, 1992, ENCYCLOPEDIA & DICTIONARY OF MEDICINE, NURSING &ALLIED HEALTH, 5th Ed., (W. B. Saunders Co.), pp. 1708 and 1651.

The method by which the compound disclosed herein can be administeredfor oral use would be, for example, in a hard gelatin capsule whereinthe active ingredient is mixed with an inert solid diluent, or softgelatin capsule, wherein the active ingredient is mixed with aco-solvent mixture, such as PEG 400 containing Tween-20. A compounddisclosed herein can also be administered in the form of a sterileinjectable aqueous or oleaginous solution or suspension. The compoundcan generally be administered intravenously or as an oral dose of 0.1 ugto 20 mg/kg given, for example, every 3-12 hours.

Formulations for oral use can be in the form of hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin. They can alsobe in the form of soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, such as peanut oil, liquid paraffinor olive oil.

Aqueous suspensions normally contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspension. Suchexcipients can be (1) suspending agent such as sodium carboxymethylcellulose, methyl cellulose, hydroxypropylmethylcellulose, sodiumalginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2)dispersing or wetting agents which can be (a) naturally occurringphosphatide such as lecithin; (b) a condensation product of an alkyleneoxide with a fatty acid, for example, polyoxyethylene stearate; (c) acondensation product of ethylene oxide with a long chain aliphaticalcohol, for example, heptadecaethylenoxycetanol; (d) a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand hexitol such as polyoxyethylene sorbitol monooleate, or (e) acondensation product of ethylene oxide with a partial ester derived fromfatty acids and hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate.

The pharmaceutical compositions can be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension can beformulated according to known methods using those suitable dispersing orwetting agents and suspending agents that have been mentioned above. Thesterile injectable preparation can also a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

A compound disclosed herein can also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient that is solid at ordinary temperature but liquid at the rectaltemperature and will therefore melt in the rectum to release the drug.Such materials include cocoa butter and polyethylene glycols.

The compounds disclosed herein as used in the methods disclosed hereincan also be administered in the form of liposome delivery systems, suchas small unilamellar vesicles, large unilamellar vesicles, andmultilamellar vesicles. Liposomes can be formed from a variety ofphospholipids, such as cholesterol, stearylamine, orphosphatidylcholines.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds disclosed herein, are employed.

In addition, some of the compounds disclosed herein can form solvateswith water or common organic solvents. Such solvates are encompassedwithin the scope of the methods contemplated herein.

B. Effective Dosages

Pharmaceutical compositions provided herein include compositions whereinthe active ingredient is contained in a therapeutically effectiveamount, i.e., in an amount effective to achieve its intended purpose.The actual amount effective for a particular application will depend,inter alia, on the condition being treated. For example, whenadministered in methods to treat thrombosis, such compositions willcontain an amount of active ingredient effective to achieve the desiredresult (e.g. decreasing the extent of the thrombosis).

The dosage and frequency (single or multiple doses) of compoundadministered can vary depending upon a variety of factors, includingroute of administration; size, age, sex, health, body weight, body massindex, and diet of the recipient; nature and extent of symptoms of thedisease being treated (e.g., the disease responsive to inhibition ofthrombin); presence of other diseases or other health-related problems;kind of concurrent treatment; and complications from any disease ortreatment regimen. Other therapeutic regimens or agents can be used inconjunction with the methods and compounds disclosed herein.

For any compound described herein, the therapeutically effective amountcan be initially determined from a variety of techniques known in theart, e.g., biochemical characterization of inhibition of thrombin, cellculture assays, and the like. Target concentrations will be thoseconcentrations of active compound(s) that are capable of decreasingthrombin enzymatic activity as measured, for example, using the methodsdescribed.

Therapeutically effective amounts for use in humans can be determinedfrom animal models. For example, a dose for humans can be formulated toachieve a concentration that has been found to be effective in animals.The dosage in humans can be adjusted by monitoring thrombin inhibitionand adjusting the dosage upwards or downwards, as described above.

Dosages can be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the methods disclosed herein, should be sufficient to affecta beneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side effects. Generally, treatment is initiated with smallerdosages, which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under circumstances is reached. In some embodiments of amethod disclosed herein, the dosage range is 0.001% to 10% w/v. In someembodiments, the dosage range is 0.1% to 5% w/v.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is entirely effective to treat the clinicalsymptoms demonstrated by the particular patient. This planning shouldinvolve the careful choice of active compound by considering factorssuch as compound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration, and the toxicity profile of the selected agent.

Accordingly, in some embodiments, dosage levels of the compoundsdisclosed herein as used in the present methods are of the order ofe.g., about 0.1 mg to about 1 mg, about 1 mg to about 10 mg, about 0.5mg to about 20 mg per kilogram body weight, an average adult weighing 70kilograms, with a preferred dosage range between about 0.1 mg to about20 mg per kilogram body weight per day (from about 0.7 mg to about 1.4gm per patient per day). The amount of the compound disclosed hereinthat can be combined with the carrier materials to produce a singledosage will vary depending upon the host treated and the particular modeof administration. For example, a formulation intended for oraladministration to humans can contain about 5 ug to 1 g of a compounddisclosed herein with an appropriate and convenient amount of carriermaterial that can vary from about 5 to 95 percent of the totalcomposition. Dosage unit forms will generally contain between from about0.1 mg to 500 mg of a compound disclosed herein.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

C. Toxicity

The ratio between toxicity and therapeutic effect for a particularcompound is its therapeutic index and can be expressed as the ratiobetween LD₅₀ (the amount of compound lethal in 50% of the population)and ED₅₀ (the amount of compound effective in 50% of the population).Compounds that exhibit high therapeutic indices are preferred.Therapeutic index data obtained from in vitro assays, cell cultureassays and/or animal studies can be used in formulating a range ofdosages for use in humans. The dosage of such compounds preferably lieswithin a range of plasma concentrations that include the ED₅₀ withlittle or no toxicity. The dosage can vary within this range dependingupon the dosage form employed and the route of administration utilized.See, e.g. Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS,Ch. 1, p. 1, 1975. The exact formulation, route of administration, anddosage can be chosen by the individual practitioner in view of thepatient's condition and the particular method in which the compound isused. For in vitro formulations, the exact formulation and dosage can bechosen by the individual practitioner in view of the patient's conditionand the particular method in which the compound is used.

VII. Examples

The examples below are meant to illustrate certain embodiments of theinvention and not to limit the scope of the invention. Abbreviationsused herein have their conventional meaning in the art, unless indicatedotherwise. Specific abbreviations include the following: Å=Ångström;Ac₂O=acetic anhydride; AcOH=acetic acid; aq=aqueous; Bt=benzotriazole;BOC=N-tert-butoxycarbonyl; br=broad; t-BuOH=tert-butanol; ° C.=degreeCelsius; d=doublet; DABCO=1,4-diazabicyclo[2.2.2]octane;DCE=1,2-dichloroethane; DCM=dichloromethane; dd=doublet of doublets;DIEA=diethylisopropylamine; DMAP=4-dimethylaminopyridine;DMF=N,N-dimethylformamide; DMSO=dimethylsulfoxide; δ=chemical shift(given in ppm, unless otherwise indicated);EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; eq=equivalent;Et₂O=diethyl ether; Et₃N=triethylamine; EtOAc=ethyl acetate;EtOH=ethanol; g=gram; h (or hr)=hour; HOBt=hydroxybenzotriazole;HPLC=high performance liquid chromatography; Hz=Hertz; IC₅₀=inhibitoryconcentration at 50% inhibition; J=coupling constant (given in Hz,unless otherwise indicated); LC=liquid chromatography; LHMDS=lithiumhexamethyldisilazide; m=multiplet; M=molar; [M+H]⁺=parent mass spectrumpeak plus H⁺; MS=mass spectrum; ms=molecular sieves; MP=melting point;Me₂NH=dimethylamine; MeOH=methanol; mg=milligram; mL=milliliter;mM=millimolar; mmol=millimole; min=minute; μL=microliter; μM=micromolar;ng=nanogram; nM=nanomolar; NMR=nuclear magnetic resonance; ppm=parts permillion; q=quartet; R_(f)=retention factor; RT=room temperature;s=singlet; t=triplet; TFA=trifluoroacetic acid; THF=tetrahydrofuran;TLC=thin layer chromatography.

Example 1—Preparation of Intermediate 1

General Scheme I.

A synthetic scheme useful for synthesis of compounds described herein isdisclosed in General Scheme I following, wherein the terms “R^(x)”,“R^(y)”, and “R^(z)” are independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, or other groups obvious to those skilled in the art.

The synthesis of Intermediate 1 followed General Procedure 1 following.

General Procedure 1

To a cold (−78° C.) solution of benzoyl chloride (5.0 mmol, 1.0 eq) andfluoroacetonitrile (278 μL, 5.0 mmol, 1.0 eq) in dry THF (15 mL) wasadded a solution of LHMDS in THF (1 M, 10 mL, 10.0 mmol, 2.0 eq). Themixture was allowed to reach room temperature, and 1N HCl was addeddropwise achieving pH 2. The mixture was concentrated under reducedpressure to afford intermediate 1 in a form pure enough for the nextstep.

Example 2—Preparation of Intermediate 2

General Procedure 1 was followed to obtain Intermediate 2. Thus, to acold (−78° C.) solution of picolinoyl chloride (5.0 mmol, 1.0 eq) andfluoroacetonitrile (278 μL, 5.0 mmol, 1.0 eq) in dry THF (15 mL) wasadded a solution of LHMDS in THF (1 M, 10 mL, 10.0 mmol, 2.0 eq). Themixture was allowed to reach room temperature, and 1N HCl was addeddropwise achieving pH 2. The mixture was concentrated under reducedpressure to afford intermediate 2 in a form pure enough for the nextstep.

Example 3—Preparation of Intermediate 3

General Procedure 1 was followed to obtain Intermediate 3. Thus, to acold (−78° C.) solution of pyran-4-carbonyl chloride (5.0 mmol, 1.0 eq)and fluoroacetonitrile (278 μL, 5.0 mmol, 1.0 eq) in dry THF (15 mL) wasadded a solution of LHMDS in THF (1 M, 10 mL, 10.0 mmol, 2.0 eq). Themixture was allowed to reach room temperature, and 1N HCl was addeddropwise achieving pH 2. The mixture was concentrated under reducedpressure to afford intermediate 3 in a form pure enough for the nextstep.

Example 4—Preparation of Intermediate 4

The synthesis of Intermediate 4 followed the procedure of GeneralProcedure 2 following.

General Procedure 2

To a solution of intermediate 1 (5.0 mmol) in ethanol (15 mL) was addedhydrazine monohydrate (582 μL, 12.0 mmol, 2.4 eq). The reaction washeated at reflux for 18 h. The reaction mixture was allowed to cool toroom temperature, and the solvent was evaporated under reduced pressure.The residue was dissolved in dichloromethane (DCM) and washed withwater. The organic phase was concentrated to give a crude product thatwas purified by silica column, yielding intermediate 4 as a light brownsolid (0.56 g, 55%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 4.80 (s, 2H),7.28-7.32 (m, 1H), 7.41-7.45 (m, 2H), 7.62-7.64 (m, 2H), 11.88 (s, 1H).

Example 5—Preparation of Intermediate 5

General Procedure 2 was followed to convert Intermediate 2 toIntermediate 5

Example 6—Preparation of Intermediate 6

General Procedure 2 was followed to convert Intermediate 3 toIntermediate 6

Example 7—Preparation of Intermediate 7

The synthesis of Intermediate 7 followed the procedure of GeneralProcedure 3 following.

General Procedure 3

A solution of intermediate 4 (12.4 mmol) and benzaldehyde (24.8 mmol, 2eq) in EtOH (20 mL) with molecular sieves (4 Å powder) was refluxed for8 h. Then was added a catalytic quantity of AcOH, NaCNBH₃ (1.6 g, 24.8mmol, 2 eq) at 0° C. with stirring for 15 h at RT. The solvent wasdistilled off, and the residue was dissolved in EtOAc (200 mL) andfiltered through a Celite® pad to remove inorganic materials. Thefiltrate was washed with saturated aqueous NaHCO₃ (2×20 mL), water (20mL), brine (20 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The resultant compound was purified by column chromatography oversilica gel (100-200 mesh) by using a solvent gradient of 0-10%MeOH—CHCl₃ as the eluent to afford Intermediate 7.

Example 8—Preparation of Intermediate 8

General Procedure 3 was followed to convert Intermediate 4 toIntermediate 8

Example 9—Preparation of Compound 23

The synthesis of Compound 23 followed the procedure of General Procedure4 following.

General Procedure 4

Pivaloyl chloride was added to a solution of Intermediate 7 intriethylamine (3 mL) at RT and stirred for 5 h. The reaction mixture wasdiluted with water (5 mL) and extracted with EtOAc (20 mL). The organiclayer washed with water (2×5 mL), saturated aqueous NaHCO₃ (5 mL), brine(5 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crudecompound was purified by column chromatography over silica gel (100-200mesh) by using a gradient mixture of 0-30% EtOAc-hexane as the eluent toafford Compound 23 (33%). MP 105-106° C.; ¹H NMR: (DMSO-d₆) δ 7.77 (d,J=7.4 Hz, 2H), 7.56-7.60 (m, 1H), 7.41-7.52 (m, 3H), 7.33-7.38 (m, 4H),7.25 (br s, 1H), 4.53 (d, J=6.2 Hz, 2H), 1.48 (s, 9H); MS: 352 [M+H]⁺.

Example 10—Preparation of Compound 10

General Procedure 4 was followed to convert Intermediate 8 to Compound10. Thus, pivaloyl chloride was added to a solution of Intermediate 8 intriethylamine (3 mL) at RT and stirred for 5 h. The reaction mixture wasdiluted with water (5 mL) and extracted with EtOAc (20 mL). The organiclayer washed with water (2×5 mL), saturated aqueous NaHCO₃ (5 mL), brine(5 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crudecompound was purified by column chromatography over silica gel (100-200mesh) by using a gradient mixture of 0-30% EtOAc-hexane as the eluent toafford Compound 10 (35%). ¹H NMR: (CDCl₃) δ 7.8-7.9 (m, 2H), 7.40-7.48(m, 3H), 7.10-7.18 (m, 1H), 6.74-6.81 (m, 2H), 4.63 (d, J=6.2 Hz, 2H),1.53 (s, 9H); MS: 392 [M+H]⁺.

Example 11—Preparation of Intermediate 9

General Procedure 3 was followed to convert Intermediate 6 toIntermediate 9

Example 12—Preparation of Compound 3

General Procedure 4 was followed to convert Intermediate 9 to Compound3. Thus, pivaloyl chloride was added to a solution of Intermediate 9 intriethylamine (3 mL) at RT and stirred for 5 h. The reaction mixture wasdiluted with water (5 mL) and extracted with EtOAc (20 mL). The organiclayer washed with water (2×5 mL), saturated aqueous NaHCO₃ (5 mL), brine(5 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The crudecompound was purified by column chromatography over silica gel (100-200mesh) by using a gradient mixture of 0-30% EtOAc-hexane as the eluent toafford Compound 3 (46%). ¹H NMR: (CDCl₃) δ 7.03 (t, J=7.0 Hz, 1H), 6.75(br s, 2H), 4.54 (d, J=6.2 Hz, 2H), 4.01-4.06 (m, 2H), 3.50-3.57 (m,2H), 2.89-2.93 (m, 1H), 1.87-1.91 (m, 4H), 1.44 (s, 9H); MS: 400 [M+H]⁺.

Example 13—Preparation of Intermediate 10

General Procedure 3 was followed to convert Intermediate 5 toIntermediate 10

Example 14—Preparation of Compound 22

General Procedure 4 was followed to convert Intermediate 10 to Compound22. Thus, pivaloyl chloride was added to a solution of Intermediate 10in triethylamine (3 mL) at RT and stirred for 5 h. The reaction mixturewas diluted with water (5 mL) and extracted with EtOAc (20 mL). Theorganic layer washed with water (2×5 mL), saturated aqueous NaHCO₃ (5mL), brine (5 mL), dried over Na₂SO₄, filtered and concentrated invacuo. The crude compound was purified by column chromatography oversilica gel (100-200 mesh) by using a gradient mixture of 0-30%EtOAc-hexane as the eluent to afford Compound 22 (40%). ¹H NMR:(DMSO-d₆) δ 8.6 (m, 1H), 7.83-7.91 (m, 2H), 7.55 (m, 1H), 7.25-7.45 (m,6H), 4.52-4.54 (m, 2H), 1.48 (s, 9H); MS: 353.03 [M+H]⁺.

The contents of all references, patents, and published applicationscited herein are hereby incorporated by reference in their entirety andfor all purposes.

While the invention has been described in detail with reference tocertain preferred embodiments thereof, it will be understood thatmodifications and variations are within the spirit and scope of thatwhich is described and claimed.

What is claimed is:
 1. A compound with structure of Formula (Ia):

or pharmaceutically acceptable salt, ester, solvate, or prodrug thereof;wherein Ring A is substituted or unsubstituted pyrazolyl; L¹ and L³ areindependently a bond, substituted or unsubstituted alkylene, substitutedor unsubstituted heteroalkylene, —S—, —SO—, —SO₂—, —O—, —NHSO₂—, or—NR⁴—; L² is absent, a bond, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, —S—, —SO—, —SO₂—, —O—,—NHSO₂—, or —NR⁴—; R¹ and R³ are independently hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstituted fusedring aryl, or substituted or unsubstituted heteroaryl; R² is absent,hydrogen, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted heterocycloalkenyl,substituted or unsubstituted aryl, substituted or unsubstituted fusedring aryl, or substituted or unsubstituted heteroaryl, provided thatwhen L² is absent, R² is absent; R⁴ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocycloalkenyl, and substituted or unsubstituted fused ring aryl orsubstituted or unsubstituted heteroaryl; and Y is a halogen.
 2. Thecompound according to claim 1, wherein L² and R² are absent.
 3. Thecompound according to claim 1, with structure of Formula (IIa) orFormula (IIb):


4. The compound according to claim 3, with structure of Formula (IIa),wherein L³ is a bond, or substituted or unsubstituted alkylene, and R³is substituted or unsubstituted aryl, substituted or unsubstituted fusedring aryl, substituted or unsubstituted heterocycloalkyl, or substitutedor unsubstituted heteroaryl, and Y is fluorine.
 5. The compoundaccording to claim 3, with structure of Formula (IIa), wherein L³ is—C(O)O—, R³ is substituted or unsubstituted alkyl, and Y is fluorine. 6.The compound according to claim 3, with structure of Formula (IIa),wherein L³ is —C(O)NR⁵—, R⁵ is hydrogen or alkyl, R³ is substituted orunsubstituted alkyl, or substituted or unsubstituted aryl, and Y isfluorine.
 7. The compound according to claim 4, wherein R³ issubstituted or unsubstituted phenyl.
 8. The compound according to claim4, wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl,thienyl, or furyl.
 9. The compound according to claim 8, wherein R³ ischloro-substituted thienyl.
 10. The compound according to claim 4,wherein said heterocycloalkyl is morpholinyl, oxanyl, or oxetanyl. 11.The compound according to claim 4, wherein said fused ring aryl isbenzodioxinyl or naphthyl.
 12. The compound according to any of claims 4to 11, wherein L¹ is a bond, —S—, —NR⁴—, substituted or unsubstitutedalkylene, or substituted or unsubstituted heteroalkylene, and R¹ ishydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted fused ring aryl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedheterocycloalkyl.
 13. The compound according to claim 12, wherein saidheteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl. 14.The compound according to claim 13, wherein R¹ is chloro-substitutedthienyl.
 15. The compound according to claim 12, wherein saidheterocycloalkyl is morpholinyl, oxanyl, or oxetanyl.
 16. The compoundaccording to claim 12, wherein said fused ring aryl is benzodioxinyl ornaphthyl.
 17. The compound according to claim 12, wherein R¹ issubstituted or unsubstituted phenyl.
 18. The compound according to claim4, wherein L² is a bond, and R² is hydrogen.
 19. The compound accordingto claim 4, wherein L² is substituted or unsubstituted alkylene or—C(O)—, and R² is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstitutedheterocycloalkenyl, substituted or unsubstituted aryl, substituted orunsubstituted fused ring aryl, or substituted or unsubstitutedheteroaryl.
 20. The compound according to claim 19, wherein saidheteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl. 21.The compound according to claim 19, wherein R² is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocycloalkyl.
 22. The compoundaccording to claim 21, wherein said heterocycloalkyl is morpholinyl,oxanyl, or oxetanyl.
 23. The compound according to claim 19, whereinsaid fused ring aryl is benzodioxinyl or naphthyl.
 24. The compoundaccording to claim 19, wherein R² is substituted or unsubstitutedphenyl.
 25. The compound according to claim 3, with structure of Formula(IIb), wherein L³ is a bond, or substituted or unsubstituted alkylene,R³ is substituted or unsubstituted aryl, substituted or unsubstitutedfused ring aryl, substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted heteroaryl, and Y is fluorine.
 26. Thecompound according to claim 3, with structure of Formula (IIb), whereinL³ is —C(O)O—, R³ is substituted or unsubstituted alkyl, and Y isfluorine.
 27. The compound according to claim 3, with structure ofFormula (IIb), wherein L³ is —C(O)NR⁵—, R⁵ is hydrogen or alkyl, R³ issubstituted or unsubstituted alkyl, or substituted or unsubstitutedaryl, and Y is fluorine.
 28. The compound according to claim 25, whereinR³ is substituted or unsubstituted phenyl.
 29. The compound according toclaim 25, wherein said heteroaryl is pyridyl, pyridazinyl, pyrimidinyl,thienyl, or furyl.
 30. The compound according to claim 29, wherein R³ ischloro-substituted thienyl.
 31. The compound according to claim 25,wherein said heterocycloalkyl is morpholinyl, oxanyl, or oxetanyl. 32.The compound according to claim 25, wherein said fused ring aryl isbenzodioxinyl or naphthyl.
 33. The compound according to any of claims25 to 32, wherein L¹ is a bond, —S—, —NR⁴—, substituted or unsubstitutedalkylene, or substituted or unsubstituted heteroalkylene, and R¹ ishydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted fused ring aryl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedheterocycloalkyl.
 34. The compound according to claim 33, wherein saidheteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl. 35.The compound according to claim 34, wherein R¹ is chloro-substitutedthienyl.
 36. The compound according to claim 33, wherein saidheterocycloalkyl is morpholinyl, oxanyl, or oxetanyl.
 37. The compoundaccording to claim 33, wherein said fused ring aryl is benzodioxinyl ornaphthyl.
 38. The compound according to claim 33, wherein R¹ issubstituted or unsubstituted phenyl.
 39. The compound according to claim25, wherein L² is a bond, and R² is hydrogen.
 40. The compound accordingto claim 25, wherein L² is substituted or unsubstituted alkylene or—C(O)—, and R² is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstitutedheterocycloalkenyl, substituted or unsubstituted aryl, substituted orunsubstituted fused ring aryl, or substituted or unsubstitutedheteroaryl.
 41. The compound according to claim 40, wherein saidheteroaryl is pyridyl, pyridazinyl, pyrimidinyl, thienyl, or furyl. 42.The compound according to claim 40, wherein R² is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocycloalkyl.
 43. The compoundaccording to claim 42, wherein said heterocycloalkyl is morpholinyl,oxanyl, or oxetanyl.
 44. The compound according to claim 40, whereinsaid fused ring aryl is benzodioxinyl or naphthyl.
 45. The compoundaccording to claim 40, wherein R² is substituted or unsubstitutedphenyl.
 46. The compound according to any of claims 1 to 45 as set forthin Table A.
 47. A pharmaceutical composition comprising a compoundaccording to any of claims 1 to 45, or a compound as set forth in TableA, and a pharmaceutically acceptable excipient.
 48. A method fortreating a disease or disorder in a subject, comprising administering acompound according to any of claims 1 to 46 or a pharmaceuticalcomposition according to claim 47, to a subject in need thereof in anamount effective to treat said disease or disorder.
 49. The methodaccording to claim 48, wherein said disease or disorder is a thromboticdisorder.
 50. The method according to claim 49, wherein said thromboticdisorder is acute coronary syndrome, venous thromboembolism, arterialthromboembolism or cardiogenic thromboembolism.
 51. The method accordingto claim 48, wherein said disease or disorder is fibrosis.
 52. Themethod according to claim 48, wherein said disease or disorder isAlzheimer's Disease.
 53. The method according to claim 48, wherein saiddisease or disorder is multiple sclerosis.
 54. The method according toclaim 48, wherein said disease or disorder is pain.
 55. The methodaccording to claim 48, wherein said disease or disorder is cancer.
 56. Amethod for preventing a disease or disorder in a subject, comprisingadministering a compound according to any of claims 1 to 46 or apharmaceutical composition according to claim 47, to a subject in needthereof in an amount effective to prevent said disease or disorder. 57.The method according to claim 56, wherein said disease or disorder is athrombotic disorder.
 58. The method according to claim 56, wherein saidthrombotic disorder is acute coronary syndrome, venous thromboembolism,arterial thromboembolism or cardiogenic thromboembolism.
 59. The methodaccording to claim 56, wherein said thrombotic disorder is disseminatedintravascular coagulation.
 60. The method according to claim 56, whereinsaid thrombotic disorder involves the presence or the potentialformation of a blood clot thrombus.